Inhibitors of cytosolic phospholipase a2

FIELD: chemistry.

SUBSTANCE: invention pertains to new compounds with general formula: , where R is -(CH2)n-A, where A: where each of B and C independently represent phenyl or phenyl substituted with 1-3 substitutes, independently chosen from a halogen, -CN, -CHO, -CF3, -OCF3, -OH, -C1-C6alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl) and -NO2; or n equals an integer from 0 to 3; n1 equals an integer from 1 to 3; n2 equals an integer from 0 to 4; n3 equals an integer from 0 to 3; n4 equals an integer from 0 to 2; X1 is chosen from a chemical bond -S-, -S(O)2-, -NH-, -NHC(O)- and -C=C-, R1 is chosen from C1-C6alkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, tetrahydropyranyl, CN, -N(C1-C6alkyl)2, phenyl, pyridinyl, pyrimidinyl, furyl, thienyl, naphtyl, morpholinyl, triazolyl, pyrazolyl, piperidinyl, pyrrolidinyl, imidazolyl, piperizinyl, thiazolydinyl, thiomopholinyl, tetrazolyl, benzoxazolyl, imidazolidine-2-thionyl, 7,7-dimethylbicyclo[2.2.1]heptane-2-onyl, benzo[1.2.5]oxadiazolyl, 2-oxa-5-azabicyclo[2.2.1]heptyl and pyrrolyl, each of which can be optionally substituted with 1-3 substitutes, independently chosen from a halogen, -CN, -CHO, -CF3, OCF3, -OH, -C1-C6alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -NO2, -SO2(C1-C3alkyl), -SO2NH2, -SO2N(C1-C3alkyl)2, -COOH, -CH2-COOH, pyridyl, 2-methylazolyl, morpholino, 1-chloro-2-methylpropyl, phenyl, (optionally substituted with one or more halogens), benzyloxy, and , X2 selected from -O-, -CH2-, -S-, -SO-, -SO2-, -NH- and , R2 represents a ring group, chosen from a phenyl or thienyl group. Each ring group is substituted with a group with formula -(CH2)n4-CO2H; and besides that, the ring group can optionally be substituted with 1 or 2 extra substitutes, independently chosen from halogen, - C1-C6alkyl and -C1-C6alkoxy; R3 is chosen from H, halogen and -NO2; R4 is chosen from H, halogen and morpholino; or its salt form, used in pharmaceuticals. The invention also relates to pharmaceutical compositions, to methods of treatment, and to compounds with formula (A).

EFFECT: obtaining new biologically active compounds and pharmaceutical compositions based on them, which have inhibiting effect on cytosolic phospholipase A2.

45 cl, 300 ex

 

The present invention relates to chemical inhibitors of the activity of various enzymes phospholipase, especially enzymes cytosolic phospholipase A2(cPLA2), and more particularly to inhibitors of the enzyme cytosolic phospholipase A2alpha (cPLA), and to new N-benzhydrylidene intermediate compounds for their preparation. The invention also relates to methods for the treatment and relief of asthma and asthma symptoms and/or symptoms of arthritic or rheumatic disorders in mammals, including humans, using data from chemical inhibitors.

Background of the invention

Leukotrienes and prostaglandins are important mediators of inflammatory processes, each of which in different ways contributed to the development of inflammatory reactions. Leukotrienes replenish the cells of inflammation, such as neutrophils, to the site of inflammation, promote extravasation of these cells and stimulate the secretion of superoxide and proteases that damage the fabric. Leukotrienes also play a pathophysiological role in hypersensitivity experienced by asthmatics [see, for example, B. Samuelson et al.,Science,237:1171-76 (1987)]. Prostaglandins increase inflammation, increasing blood flow and, consequently, infiltration of leukocytes to sites of inflammation. Prostaglandins also increase olvwu reaction, caused by a stimulus.

Prostaglandins and leukotrienes are unstable and are not stored in cells, but instead are synthesized [W.L. Smith,Biochem. J.,259:315-324 (1989)] from arachidonic acid in response to the impact of the stimulus. Prostaglandins are produced from arachidonic acid by the action of enzymes MOR-1 and MOR-2. Arachidonic acid is also a substrate for the particular enzyme of the pathway to obtaining leukotrienes.

Arachidonic acid, which enters the data two different ways inflammatory process, stands out from the sn-2 position of membrane phospholipids by the enzyme phospholipase A2(in the future PLA2). It is believed that catalyzed PLA2the reaction is limiting the speed stage in the process of biosynthesis, mediators which are lipids, and production of inflammatory prostaglandins and leukotrienes. When the phospholipid substrate PLA2belongs to phosphatidylcholine class with essential bridge in the sn-1 position produced lysophospholipid is the immediate predecessor factor, platelet-activating (hereafter referred to as PAF), another powerful mediator of inflammation [S.I. Wasserman, Hospital Practice, 15:49-58 (1988)].

Most anti-inflammatory therapies focuses on preventing the production of prostaglandins, or lei is Adrianov data in different ways, but not on prevention products and those of others. For example, ibuprofen, aspirin and indomethacin are nonsteroidal anti-inflammatory drugs, which inhibit the production of prostaglandins by inhibiting COX-1/COX-2, but have no effect on inflammatory production of leukotrienes from arachidonic acid in other ways. On the contrary, zileuton inhibits only way the conversion of arachidonic acid to leukotrienes, without affecting the production of prostaglandins. None of these widely used anti-inflammatory drugs have no effect on the production of PAF.

Therefore, direct inhibition of the activity of PLA2it was put forward as a useful mechanism for the medicinal product, i.e. to inhibit the inflammatory response. [See, for example, J. Chang et al.,Biochem. Pharmacol.36: 2429-2436 (1987).]

Family PLA2enzymes characterized by the presence of a secretion signal directed and, ultimately, secreted from the cells, was ordered and structurally determined. Data is secreted PLA2have a molecular mass of approximately 14 kDa and contain seven disulfide bonds that are required for activity. Data PLA2found in huge amounts in the pancreas of mammals, the venom of bees and various snake venoms. [With the., for example, references 13-15 quoted above in the work of J. Chang et al. and E.A. Dennis,Drug Devel. Res.,10:205-220 (1987).] However, the pancreatic enzymes are considered to have a digestive function in and of themselves should not play an important role in the production of inflammatory mediators, whose products should be strictly regulated.

Was determined the primary structure of the first not human pancreatic PLA2. This is not pancreatic PLA2found in platelets, synovial fluid and spleen and is also a secretory enzyme. This enzyme is a member of the above family. [Cm. J.J. Seilhamer et al.,J. Biol.Chem.,264: 5335-5338 (1989), R. Kramer et al.,J. Biol. Chem.,264:5768-5775 (1989) and A. Kando et al.,Biochem. Biophys. Res. Comm.,163: 42-48 (1989).] However, it is doubtful that this enzyme is important in the synthesis of prostaglandins, leukotrienes and PAF, not because pancreatic PLA2is an extracellular protein, which would be difficult to regulate, and the following enzymes in the biosynthesis pathway for these compounds are intracellular proteins. Moreover, there is evidence that PLA2regulated protein protein kinase C and G [R. Burch, J. Axelrod,Proc. Natl. Acad. Sci. U.S.A.,84: 6374-6378 (1989)], which are cytosolic proteins that must act on intracellular proteins. It would be impossible to not pankreaticheskogo PLA 2to function in the cytosol because of the high reduction potential restore disulfide bonds and have disabled the enzyme.

Mouse PLA2was identified in macrophages cell lines mice indicated RAW 264.7. Specific activity equal to 2 mol/min/mg, resistant to reducing conditions, as reported, was associated with a molecule having a molecular weight of about 60 kDa. However, this protein was not purified to homogeneity. [Cm. C.C. Leslie et al.,Biochem. Biophys. Acta.,963:476-492 (1988).] Quoted above link is included here by reference for information relating to the functions of the enzymes phospholipase, in particular PLA2.

Cytosolic phospholipase A2alpha (hereinafter ″cPLA2α″) also was identified and cloned. [Cm. U.S. patent No. 5322776 and 5354677, which are incorporated here by reference in its entirety.] The enzymes of these patents are intracellular PLA2enzymes isolated from its natural source or obtained in purified form otherwise, which are intracellular, producing arachidonic acid in response to an inflammatory stimulus.

Now that you have identified several enzymes phospholipase, it would be desirable to identify chemical inhibitors of the action of specific enzymes phospholipase, the rich, these inhibitors could be used for the treatment of inflammatory conditions in particular, in cases where it is desirable to suppress the production of prostaglandins, leukotrienes and PAF. There remains a need to identify such anti-inflammatory agents for therapeutic use in various painful conditions and intermediates for their preparation.

DETAILED description of the INVENTION

This invention covers compounds of formula (I):

where

R is selected from the formula -(CH2)n-A, -(CH2)n-S-A or -(CH2)n-O-A, where A is selected from the group:

where

D represents C1-C6lower alkyl, C1-C6lower alkoxy, C3-C6cycloalkyl, -CF3or -(CH2)1-3-CF3;

B and C are independently selected from phenyl, pyridinoline, pyrimidinyl, fernilee, tofanelli or pyrrolidino groups, each of which is optionally substituted 1-3, preferably 1-2 substituents, independently selected from H, halogen, -CN, -CHO, -CF3, -OCF3, -OH, -C1-C6of alkyl, -C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-(C1-C6alkyl), -NO2or 5 - or 6-membered heterocyclic or heteroaromatic ring containing 1 or 2 heteroatom which is s selected from O, N or S; or

n is an integer from 0 to 3;

n1an integer from 1 to 3;

n2an integer from 0 to 4;

n3an integer from 0 to 3;

n4an integer from 0 to 2;

X1selected from a chemical bond, -S-, -O-, -S(O)-, -S(O)2-, -NH-, -NHC(O)-, -C=C-,

R1is a group selected from C1-C6alkyl, C1-C6fluorinated alkyl, C3-C6cycloalkyl, tetrahydropyranyl, campaniles, Adamantine, CN, -N(C1-C6alkyl)2, phenyl, pyridinoline, pyrimidinyl, furillo, thienyl, naftilos, morpholinyl, triazoline, pyrazolidine, piperidinyloxy, pyrrolidinyloxy, imidazolidine, piperazinilnom, thiazolidinones, thiomorpholine, tetrazole, indole, benzoxazole, benzofuranol, imidazolidin-2-tikovoi, 7,7-dimethylbicyclo[2.2.1]heptane-2-about, benzo[1.2.5]oxadiazole, 2-oxa-5-azabicyclo[2.2.1]heptane, piperazine-2-about or pyrrolidino groups, each of which is optionally substituted 1-3, preferably 1-2 substituents, independently selected from H, halogen, -CN, -CHO, -CF3, -OCF3, -OH, -C1-C6of alkyl, -C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-(C1-C6and the Kil) -NO2, -SO2(C1-C3alkyl), -SO2NH2, -SO2NH(C1-C3alkyl), -SO2N(C1-C3alkyl)2, -COOH, -CH2-COOH, -CH2-N(C1-C6alkyl), -CH2-N(C1-C6alkyl)2, -CH2-NH2, pyridine, 2-methylthiazole, morpholino, 1-chloro-2-methylpropyl, -C1-C6thioalkyl, phenyl (optionally optionally substituted by halogen), benzyloxy, -(C1-C3alkyl)C(O)CH3-(C1-C3alkyl)OCH3, -C(O)NH2or

or

X2selected from-O-, -CH2-, -S-, -SO-, -SO2-, -NH-, -C(O)-,

R2represents a ring group selected from phenyl, pyridinoline, pyrimidinyl, furillo, thienyl or pyrrolidino group and ring group substituted by a group of the formula -(CH2)n4-CO2H or a pharmaceutically acceptable acid mimic or mimetic compound; and, in addition, optionally substituted by 1 or 2 additional substituents, independently selected from H, halogen, -CN, -CHO, -CF3, -OCF3, -OH, -C1-C6of alkyl, -C1-C6alkoxy, -C1-C6thioalkyl, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-(C1-C6alkyl) or-NO2;

R3selected from H, halogen, -CN, -CHO, -CF3, -OCF3, -OH, -C1-C6of alkyl, -C1-C6alkoxy, -C1-C6thioalkyl, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-(C1-C6alkyl) or-NO2;

R4selected from H, halogen, -CN, -CHO, -CF3, -OCF3, -OH, -C1-C6of alkyl, -C1-C6alkoxy, -C1-C6thioalkyl, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-(C1-C6alkyl), -NO2, -N-C(O)-N(C1-C3alkyl)2, -N-C(O)-NH(C1-C3alkyl), -N-C(O)-O-(C1-C3alkyl)2, -SO2-C1-C6of alkyl, -S-C3-C6cycloalkyl, -S-CH2-C3-C6cycloalkyl, -SO2-C3-C6cycloalkyl, -SO2-CH2-C3-C6cycloalkyl, -C3-C6cycloalkyl, -CH2-C3-C6cycloalkyl, -O-C3-C6cycloalkyl, -O-CH2-C3-C6cycloalkyl, phenyl, benzyl, benzyloxy, morpholino or other heterocycles, such as pyrrolidine, piperidine, piperazine, furan, thiophene, imidazole, tetrazole, pyrazin, pyrazolone, pyrazole, imidazole, oxazole or isoxazol, and the cycles of each of the data R4groups optionally substituted by 1-3 substituents selected from the group H, halogen, -CN, -CHO, -CF3, -O, -C1-C6of alkyl, -C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-(C1-C6alkyl), -NO2, -SO2(C1-C3alkyl), -SO2NH(C1-C3alkyl), -SO2N(C1-C3alkyl)2or-OCF3;

or pharmaceutically acceptable salt form.

You must understand that With1-C6fluorinated alkyl groups in the definition of R1can be any alkyl group containing from 1 to 6 carbon atoms with any number of substituents, represents fluorine, including, but not limited to, -CF3, alkyl chain containing from 1 to 6 carbon atoms, with the end triptorelin group-CF2CF3etc.

Ester forms of these compounds include pharmaceutically acceptable ester form, known from the prior art, including forms, which can be converted in the body during metabolism in the free acid form, such as free carboxyl form, for example, according to the invention it is possible to use the corresponding alkyl esters, cycloalkyl esters, aryl esters and their heterocyclic analogues, where alkyl esters, cycloalkyl esters and aryl esters are what I preferred and alcohol residues may have additional substituents. Especially preferred are C1-C8alkyl esters, preferably C1-C6alkyl esters such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentalogy ester, isopentylamine ester, neopentylene ester, hexyl ester, cyclopropylethyl ester, cyclopropylmethyl ester, cyclobutylamine ester, cyclopentyloxy ester, cyclohexyloxy ester, or aryl esters such as phenyl ester, benzyl ester or tallowy ester.

In the definition of X1have in mind that Alchemilla bridge group-C=C - represents a CIS - or TRANS-orientation shown(s) connection(s).

Pharmaceutically acceptable acid mimic or mimetic compounds applicable in the compounds of the present invention, include compounds where R2selected from the group:

(acid mimetic compounds shown attached to the phenyl)

where Rachosen from-CF3, -CH3, phenyl or benzyl, with the phenyl or benzyl group is optional what about substituted by 1-3 groups selected from-C1-C6of alkyl, -C1-C6alkoxy, -C1-C6thioalkyl, -CF3, halogen, -OH or-COOH; Rbchosen from-CF3, -CH3, -NH2, phenyl or benzyl, with the phenyl or benzyl group optionally substituted by 1-3 groups selected from-C1-C6of alkyl, -C1-C6alkoxy, -C1-C6thioalkyl, -CF3, halogen, -OH or-COOH; and Rcchosen from-CF3or-C1-C6the alkyl.

In the compounds of the present invention, its subgroups and intermediate compounds examples of variables is the following:

Example R is -(CH2)n-A, for example, where n is 0 and/or A represents a group

where B and C are as defined in the present description.

Examples of each of B and C independently are unsubstituted phenyl, pyridinoline, pyrimidinyl, furilla, thienyl or pyrrolidine group, for example, where A represents a group:

Examples R3selected from H, halogen, -CN, -CHO, -CF3, -OH, -C1-C6of alkyl, -C1-C6alkoxy, -C1-C6thioalkyl, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-(C1-C6alkyl), and-NO2.

Examples Rsub> 4selected from H, halogen, -CN, -CHO, -CF3, -OH, -C1-C6of alkyl, -C1-C6alkoxy, -C1-C6thioalkyl, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-(C1-C6alkyl), -NO2morpholino or other heterocycles, such as pyrrolidine, piperidine, piperazine, furan, thiophene, imidazole, tetrazole, pyrazin, pyrazolone, pyrazole, imidazole, oxazole and isoxazol.

In some embodiments, implementation of R3and R4attached to the 5 and 6 position of the indole ring.

An example of n3is 1.

Examples X2are-O-, -SO2-, -NH - and-CH2-.

Examples R2are groups chosen from:

or pharmaceutically acceptable acid mimic or mimetic compounds, where n4is 0-2 and

R8and R9independently selected from H, halogen, -CN, -CHO, -CF3, -OH, -C1-C6of alkyl, -C1-C6alkoxy, -C1-C6thioalkyl, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-(C1-C6alkyl) or-NO2.

An example of n4is 0.

In some embodiments, implementation of -(CH2)n4-CO2H group, or a pharmaceutically acceptable acid mimic or mimetic is connected to the I are in the position 4 of the phenyl ring.

Examples n1are the integers 1 or 2. Examples n2are 0, 1 or 2; for example, n1and n2both can be equal to 1.

X1for example, can be selected from a chemical bond, -S-, -O-, -NH - or-N(C1-C3alkyl)-.

Examples R1are1-C6alkyl, C3-C6cycloalkyl, phenyl, pyridinyl, naphthyl, tetrazol, each of which is optionally substituted by 1-3 substituents, independently selected from H, halogen, -CN, -CHO, -CF3, -OCF3, -OH, -C1-C6of alkyl, -C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-(C1-C6alkyl), -NO2, -SO2(C1-C3alkyl), -SO2NH2, -SO2NH(C1-C3alkyl), -SO2N(C1-C3alkyl)2, -COOH, -CH2-COOH, -CH2-N(C1-C6alkyl), -CH2-N(C1-C6alkyl)2, -CH2-NH2- 1-C6thioalkyl, phenyl (optionally optionally substituted by halogen), benzyloxy, -(C1-C3alkyl)C(O)CH3-(C1-C3alkyl)OCH3and-C(O)NH2.

In some embodiments, implementation of R1has the formula:

where R5, R6and R6'independently selected from H, halogen, -CN, -CHO, -CF3, -OCF3, -OH, -C1/sub> -C6of alkyl, -C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-(C1-C6alkyl), and-NO2.

The first subgroup of compounds according to this invention, or pharmaceutical salts include compounds of the above groups, where A is a fragment:

and B, C, n, n1n2n3n4, R, X1X2, R1, R2, R3and R4are as defined above.

The second subgroup of compounds according to this invention includes compounds of the above first subgroup, where B and C are unsubstituted phenyl, pyridinyl, pyrimidinyl, follow, thienyl or pyrrolidino group and R, n, n1n2n3n4, R1X1X2, R2, R3and R4are as defined above.

The third subgroup of compounds and pharmaceutically acceptable salt forms according to this invention includes compounds of the above second subgroup, where A is a fragment:

and n, n1n2n3n4, R, X1X2, R1, R2, R3and R4are as defined above.

The fourth subgroup of compounds according to this invention including the em compounds of formula (II) or (III):

where n1n2n3n4X1X2, R1, R2, R3and R4are as defined above, or its pharmaceutically acceptable salt.

The fifth subgroup of compounds according to this invention includes compounds of formula (II) or (III), where n3=1 and n1n2n4X1X2, R1, R2, R3and R4are as defined above, or its pharmaceutically acceptable salt.

The sixth subgroup of compounds according to this invention includes compounds of the above fifth sub-groups, where R2represents phenyl substituted by a group of the formula -(CH2)n4-CO2H, and optionally substituted 1 or 2 additional substituents, independently selected from H, halogen, -CN, -CHO, -CF3, -OH, -C1-C6of alkyl, -C1-C6alkoxy, -C1-C6thioalkyl, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-(C1-C6alkyl) or-NO; and n1, n2, n4, R1X1X2, R2, R3and R4are as defined above, or its pharmaceutically acceptable salt.

Seventh subgroup of compounds according to this invention includes compounds of formula (IV) or (V):

where

n1presented yet an integer from 1 to 3;

n2is an integer from 1 to 3;

R5, R6and R6'independently selected from H, halogen, -CN, -CHO, -CF3, -OCF3, -OH, -C1-C6of alkyl, -C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-(C1-C6alkyl) or-NO2;

X1selected from a chemical bond, -S-, -O-, -NH - or-N-(C1-C3alkyl)-;

X2selected from-O-, SO2or-CH2-;

R2is a fragment selected from the group:

R8and R9independently selected from H, halogen, -CN, -CHO, -CF3, -OH, -C1-C6of alkyl, -C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-(C1-C6alkyl) or-NO2;

n4an integer from 0 to 2;

R3selected from H, halogen, -CN, -CHO, -CF3, -OH, -C1-C6of alkyl, -C1-C6alkoxy, -C1-C6thioalkyl, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-(C1-C6alkyl) or-NO2; and

R4selected from H, halogen, -CN, -CHO, -CF3, -OH, -C1-C6of alkyl, -C1-C6alkoxy, -C1-C6thioalkyl, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-(C1 -C6alkyl), -NO2morpholino or other heterocycles, such as pyrrolidine, piperidine, piperazine, furan, thiophene, imidazole, tetrazole, pyrazin, pyrazolone, pyrazole, imidazole, oxazole or isoxazol;

or their pharmaceutically acceptable salt forms.

The eighth subgroup of compounds according to this invention includes compounds of formula (VI) or (VII):

where

X1selected from a chemical bond, -S-, -O-, -NH - or-N-(C1-C3alkyl)-;

X2selected from-O-, -SO2- or-CH2-;

R3selected from H, halogen, -CN, -CHO, -CF3, -OH, -C1-C6of alkyl, -C1-C6alkoxy, -C1-C6thioalkyl, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-(C1-C6alkyl) or-NO2; and

R4selected from H, halogen, -CN, -CHO, -CF3, -OH, -C1-C6of alkyl, -C1-C6alkoxy, -C1-C6thioalkyl, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-(C1-C6alkyl), -NO2morpholino or other heterocycles, such as pyrrolidine, piperidine, piperazine, furan, thiophene, imidazole, tetrazole, pyrazin, pyrazolone, pyrazole, imidazole, oxazole or isoxazol;

n1an integer from 1 to 2;

n2an integer from 1 to 2;

R5, R6The R 6'independently selected from H, halogen, -CN, -CHO, -CF3, -OCF3, -OH, -C1-C6of alkyl, -C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-(C1-C6alkyl) or-NO2;

R8and R9independently selected from H, halogen, -CN, -CHO, -CF3, -OH, -C1-C6of alkyl, -C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-(C1-C6alkyl) or-NO2;

or their pharmaceutically acceptable salt forms.

Ninth subgroup of compounds according to this invention includes compounds of formula (VI) or (VII), where n1is 1; n2equal to 1 and X1X2, R3, R4, R5, R6, R6', R8and R9are as defined in the above eighth sub-group, or their pharmaceutically acceptable salt forms.

The tenth subgroup of compounds according to this invention includes compounds of the above ninth subgroup, where X1represents a chemical bond, n1n2X2, R3, R4, R5, R6, R6', R8and R9are as defined in the above ninth subgroup, or their pharmaceutically acceptable salt forms.

Eleventh subgroup of compounds according to this izobreteny which includes compounds of formula (VIII) or (IX)

or

where

n1an integer from 1 to 3;

n20;

X1represents a chemical bond;

n3, n4, X2, R1, R2, R3and R4are as defined above, or its pharmaceutically acceptable salt.

Twelfth subgroup of compounds according to this invention includes compounds of formula (X) or (XI)

where

n1an integer from 1 to 3;

n20;

R5, R6and R6'independently selected from H, halogen, -CN, -CHO, -CF3, -OCF3, -OH, -C1-C6of alkyl, -C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-(C1-C6alkyl) or-NO2;

X1represents a chemical bond;

X2selected from-O-, -SO2- or-CH2-;

R2is a fragment selected from the group:

R8and R9independently selected from H, halogen, -CN, -CHO, -CF3, -OH, -C1-C6of alkyl, -C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-(C1-C6alkyl) or-NO2;

n4is generally the number from 0 to 2;

R3selected from H, halogen, -CN, -CHO, -CF3, -OH, -C1-C6of alkyl, -C1-C6alkoxy, -C1-C6thioalkyl, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-(C1-C6alkyl) or-NO2; and

R4selected from H, halogen, -CN, -CHO, -CF3, -OH, -C1-C6of alkyl, -C1-C6alkoxy, -C1-C6thioalkyl, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-(C1-C6alkyl), -NO2morpholino or other heterocycles, such as pyrrolidine, piperidine, piperazine, furan, thiophene, imidazole, tetrazole, pyrazin, pyrazolone, pyrazole, imidazole, oxazole or isoxazol;

or their pharmaceutically acceptable salt forms.

Thirteenth subgroup of compounds according to this invention includes compounds of formula (XII) or (XIII):

where

X1represents a chemical bond;

X2selected from-O-, -SO2- or-CH2-;

R3selected from H, halogen, -CN, -CHO, -CF3, -OH, -C1-C6of alkyl, -C1-C6alkoxy, -C1-C6thioalkyl, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-(C1-C6alkyl) or-NO2; and

R4selected from H, halogen, -CN, -CHO, CF 3, -OH, -C1-C6of alkyl, -C1-C6alkoxy, -C1-C6thioalkyl, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-(C1-C6alkyl), -NO2morpholino or other heterocycles, such as pyrrolidine, piperidine, piperazine, furan, thiophene, imidazole, tetrazole, pyrazin, pyrazolone, pyrazole, imidazole, oxazole or isoxazol;

n1an integer from 1 to 2;

n20;

R5, R6and R6'independently selected from H, halogen, -CN, -CHO, -CF3, -OCF3, -OH, -C1-C6of alkyl, -C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-(C1-C6alkyl) or-NO2;

R8and R9independently selected from H, halogen, -CN, -CHO, -CF3, -OH, -C1-C6of alkyl, -C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-(C1-C6alkyl) or-NO2;

or their pharmaceutically acceptable salt forms.

Compounds according to the invention can be used for treating, suppressing, alleviate or ameliorate asthma and asthmatic conditions. Methods of treating, suppressing, alleviate or ameliorate asthma and asthmatic conditions in this invention include methods of treating acquired bronchial speakers who we (also known as allergic asthma or atopic asthma), hereditary asthma (also known as non-allergic asthma or Autopista bronchial asthma) or their combinations, which are called mixed asthma. Condition of patients experiencing or exposed to acquired or allergic bronchial asthma, include cases caused by or associated with many allergens, such as pollen, spores, grass or cornice, pet dander, dust, mites, etc. Due to the fact that allergens and other irritants by themselves are present at various points during the year, these types of cases also called seasonal asthma. The group acquired asthma also includes an bronchial asthma and allergic aspergillosis of the bronchi and lungs.

Hereditary asthma, which can be treated or to facilitate these methods include cases caused by infectious agents, such as those that cause colds and flu in adults and respiratory syncytial virus (RSV), rhinovirus and influenza virus, common in children. Also included asthmatic condition that can be caused by some asthmatics exercise and/or cold air. The methods are applicable for hereditary asthma associated with industrial or professional effects such as smog, ozone, harmful the e gases, sulfur dioxide, nitrogen oxides, fumes, including isocyanates, evaporation paints, plastics, polyurethanes, varnishes, etc., wood, vegetable dust or other organic dust, etc. Methods are also applicable for asthma cases associated with food additives, preservatives and drugs. Normal substances data types include food dyes such as tartrazine, preservatives, similar to bisulfite and metabisulfite, and pharmacological agents, such as aspirin and nonsteroidal anti-inflammatory drugs (NSAID). Also included are methods of treating, suppressing or alleviating types of asthma, called hidden asthma or cough variant asthma.

The described methods are also applicable for the treatment or relief of hereditary asthma associated with gastroesophageal reflux (GERD), which can stimulate bronchostenosis. GERD, together with retained secretions of the body, suppress cough and exposure to allergens and irritants in the bedroom, can contribute to the asthmatic condition called nocturnal asthma or Noctumal asthma. Ways to treat, suppress or alleviate asthma associated with GERD, pharmaceutically effective amount of the compounds of this invention can be used, as described here,in combination with a pharmaceutically effective amount of drug for the treatment of GERD. These drugs include, but are not limited to, proton pump inhibitor similar to tablets pantoprazole sodium prolonged action brand PROTONIX®, capsules omeprazole prolonged action brand PRILOSEC®, tablets rabeprazole of sodium acting brand ACIPHEX® or capsules lansoprazole prolonged action brand PREVACID®. It is clear that pharmaceutically effective amount of these drugs include amounts described in the conventional medical literature, including pharmaceutically effective dosage and method of application of these preparations, described in 2001 Physicians' Desk Reference (55 Edition, Medical Economics Company, Montvale, New Jersey 07645-1742.

Compounds and methods according to this invention is applicable for the treatment, relief, suppression and easing arthritic conditions in mammals. Methods according to this invention include relief, suppression, mitigation and treatment in mammals, arthritic conditions, including, but not limited to, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, infectious arthritis, osteoarthritis (which includes erosive osteoarthritis and also known as artresources, or degenerative arthritis or DJD), systemic lupus erythematosus and disease Steele. Each of these way which includes an introduction to a mammal in need of such action pharmaceutically effective amount of a substituted indole according to the invention, as described here, or its pharmaceutically acceptable salt or ester form.

The methods of this invention include methods of treating arthritic conditions associated with spondylitis, including ankylosing spondylitis, reactive arthritis (Reiter syndrome), psoriatic arthritis, arthritis associated with chronic inflammatory bowel disease and is associated with AIDS seronegative spondyloarthropathies.

The invention also provides methods of treatment, mitigation or suppression of rheumatic diseases and disorders. These methods are applicable for the treatment of systemic lupus erythematosus, systemic sclerosis and scleroderma, polymyositis, dermatomyositis, necrotizing vasculitis, and other vasculopathy, hypersensitive vasculitis (including disease Seleina's disease, Wegener's granulomatosis, Takayasu giant cells, Muco-cutaneous lymph syndrome (Kawasaki disease), syndrome behceta, cryoglobulinemia, juvenile dermatomyositis, Sjogren syndrome, overlapping syndromes (including mixed diffuse connective tissue disease), rheumatic polymyalgia, erythema, recurring polyandria, tendonitis (tenosynovitis), tendinite twin peak muscles, bursitis, bursitis olecranon, course of adhesive capsulitis shoulder (scapula-humerus is periarthritis), springy fingers and Whipple's disease.

Compounds according to this invention is also applicable to the treatment, mitigation or suppression of disease, metabolic or endocrine diseases with rheumatic conditions, including gout, pseudogout, chondrocalcinosis, amyloidosis, scurvy, specific condition of deficiency of enzymes (including Fabry disease, alkaptonuria, Kronos syndrome Lesch-Nyana and Gaucher disease), hyperlipoproteinemy (types II, IIa, IV), the syndrome Ehler-Danlos syndrome, Marfan syndrome, elastic pseudoxanthoma, Wilson's disease. In addition, these methods can treat rheumatic conditions associated with endocrine diseases such as diabetes mellitus, acromegaly, hyperparathyroidism, references for additional information progressive myositis syndrome hypermodernity, congenital complex arthrogryposis and thyroid gland diseases, such as strumitis, tereos and graves ' disease. These methods can also be used in rheumatic conditions associated with tumors, such as primary tumor (sinovioma), metastatic tumors, multiple myeloma, leukemia and lymphoma, pigment villonodular synovitis, osteochondromatous and others. As the methods of the present invention also includes the relief of rheumatic conditions associated with neuropathic disorders is, including joints Charcot syndrome shake hands (also known as syndrome clenched fingers, caused by vibration, or Raynaud's syndrome), repeated stress syndromes, reflex sympathetic dystrophy and compression neuropathies, such as peripheral infringement (including carpal tendon syndrome, predatory syndrome, upper aperture and tarsal tunnel syndrome, radiculopathy, and narrowing of the spinal canal.

Compounds and methods according to this invention is applicable for the treatment, relief and suppression of these States, pain and inflammation, with which they are associated. Methods of treatment, reduce, suppress or alleviate these conditions in a mammal includes the introduction to a mammal in need of such activity pharmaceutically effective amount of the compounds according to this invention, one or in combination with another drug, such as anti-rheumatic, anti-inflammatory or analgesic pharmaceutical agent.

A further method for the treatment of asthma according to this invention comprises the administration to a mammal in need of such treatment a pharmaceutically effective amount of the compounds according to this invention, as described above, and a pharmaceutically effective amount of one or more additional prorivaetm the political preparations.

Antiasthmatic drugs applicable to these combinations include medical long-acting drugs, such as corticosteroids (glucocorticoids), sodium kromolin-(disubstituted sodium cromoglycate - DSCG), nedocromil, methylxanthines (such as theophylline and leukotriene modifiers. Applicable modifiers include leukotriene receptor antagonists leukotriene such as zafirlukast (ACCOLATE®) and montelukast (SINGULAIR®), and inhibitors of 5-lipoxygenase, such as zileuton (ZYFLO®). Applicable corticosteroids include inhaled products, such as beclomethasone dipropionate, budesonide, flunisolide, fluticasone, and triamcinolone, and their pharmaceutically acceptable salt forms. Also applicable are systemic corticosteroids, such as prednisone, prednisolone and methylprednisolone.

Also applicable are Antiasthmatic drugs fast action, such as beta2agonists prolonged action, short-acting beta2agonists, anticholinergics, and systemic corticosteroids. β-adrenergic tools that you can use include epinephrine, isoproterenol, metaproterenol, terbutaline, isoetharine, albuterol, bitolterol and pirbuterol. Applicable anticholinergics include atropine (is it derived ipatropium bromide and glycopyrrolate. Compounds according to this invention can also be used to treat asthma in conjunction with immunotherapy allergies, often called hypoinsulinaemia therapy. These compounds can be introduced in accordance with the doses and requirements known from the prior art.

Additional asthma medications that can be used in combination with this invention include pranlukast, anakinra, seratrodast, olopatadine hydrochloride, chromoglycate Liestal, ramatroban, the receptor for interleukin-4 (immunex), urodilatin, colforsin daropate, salbutamol, LCB-2183, andolast, ciclesonide, budesonide, formoterol, omalizumab, tranilast, saredutant, CDP-835 (anti-IL-5 Mab), Fexofenadine HCl, N-(1-(chlorophenyl)-1-methylethyl)-3-(imidazol-1-yl)propilenglikolem (BTS-71-321), cilomilast, bimosiamose, corticotropin-releasing factor, clenoliximab, Tiotropium bromide, 2H-1,2-benzoylation, 3,4-dihydro-4,4-dimethyl (BXT-51072), trilepton, (R)-salbutamol, 8-methoxyquinoline-5-(N-(2,5-dichloropyridine-3-yl))carboxamide (D-4418), triamcinolone acetonide, KW-4490 (KF-19514), LAX-300 (LX-109), IDEC-152 (ST-152; anti-CD-23 antibody), cytokine Traps, anandamide, SRL-172, salmeterol + fluticasone, KCA-757, 2-pyridylcarbonyl acid, 6-(2-(3,4-dioxyphenyl)-4-thiazolyl)-(OPC-6535), PM-56D9, salbutamol, CT-2820 (PDEIV inhibitors), beclometasone, nepadutant, ketotifen fumarate, DHEAS (PB-005), Pharmaprojects No. 5163, No. 5278 and No. 5297, salbuta the l sulfate, EPI-2010 (EpiGenRx), mepolizumab, benzamide, N-(5-(3-((4-chlorophenyl)sulfonyl)propyl)-2-(1H-tetrazol-5-ylethoxy)phenyl)-3-((4-(1,1-dimethylethyl)-2-thiazolyl)methoxy)-, one-deputizing the sodium salt of (YM-158), 2-(4-ethoxycarbonylmethyl)-6-(3,4-acid)-2,3,4,5-tetrahydropyrazin-3-one Pharmaprojects No. 5450), Sch-205528, L-826141 (Pharmaprojects No. 5477), budesonide, garamycin, sodium salt of 4,4-bis(4-(quinoline-2-ylethoxy)phenyl)pentanol acid (VML-530), the inhibitor of IL-9, beclomethasone dipropionate, formoterol, cyclo(MePhe-Leu-Asp-Val-D-Arg-D-Arg) (ZD-7349), salbutamol, ethanaminium, 2-(((2-acetyl-4-((1-oxohexanoyl)amino)phenoxy)hydroxyphenyl)oxy)-N,N,N-trimethyl-, inner salt (CPR-2015), PD-168787 (CI-1018), inhibitors of cathepsin S, SB-240683 (anti-IL-4 Mab), BIIL-284, APC-2059, budesonide + formoterol, Bay-16-9996 (antagonist IL-4), beclomethasone, GW-328267, antagonists of VLA-4, 4-hydroxy-1-methyl-3-octyloxy-7-cinepanorama-2(1H)-chinoline (TA-270), CpG-7909 (ProMune), DNK-333A (Pharmaprojects No. 6070), AWD-12-281, LM-1507 (LM-1484), formoterol, MOL 6131, inhibitors of cathepsin S, CS-615, ibudilast, 2-{N-(4-(4-chlorophenylsulfonyl)butyl)-N-{3-(2-(4-cyclobutylmethyl-2-yl)ethyl)benzyl}sulfamoyl}benzoic acid (S-36527) and 2-{N-(4-(4-chlorophenylsulfonyl)butyl)-N-{3-((4-isopropylthiazole-2-yl)metiloksi)benzyl}sulfamoyl}benzoic acid (S-36496).

This invention also includes pharmaceutical compositions comprising a pharmaceutically effective amount of the compounds of this invention or its headlight is asepticheski acceptable salt form, and one or more pharmaceutically acceptable carriers or excipients.

Compounds of the present invention can be used in a pharmaceutical composition when combined with a pharmaceutically acceptable carrier. This composition may also contain (in addition to the compound or compounds of the present invention and a carrier) diluents, fillers, salts, buffers, stabilizers, substances that increase the solubility, and other materials well known in the prior art. The term ″pharmaceutically acceptable″ denotes a non-toxic substance that does not interfere with the implementation of the biological activity of the active(s) ingredient(s). Characteristics of the carrier will depend on the method of introduction. The pharmaceutical composition may additionally contain other anti-inflammatory agents. Such additional factors and/or agents can be included in the pharmaceutical composition, to obtain a synergistic effect with the compounds of the present invention, or to minimize side effects caused by the compound of the present invention.

The pharmaceutical composition according to the invention may be in the form of liposomes, in which the compounds of the present invention is combined, in addition to other pharmaceutically acceptable carriers, the amphipatic agent, such as lipids that exist in aggregated form as micelles, insoluble monolayers, liquid crystals, or lamellar layers in aqueous solution. Suitable lipids for liposomal formulation include, without limitation, monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponin, bile acids and similar compounds. The receipt of such liposomal formulations is known in the art and is described, for example, in U.S. patent No. 4235871, U.S. patent No. 4501728, U.S. patent No. 4837028 and U.S. patent No. 4737323, each of which is included here by reference.

Used herein, the term ″pharmaceutically effective amount″ or ″a therapeutically effective amount″ indicate the total amount of each active component of the pharmaceutical composition or method that is sufficient to show a significant benefit for the patient, i.e. treatment, healing, prevention, inhibition or enhancement of the physiological response or condition, such as a state of inflammation or pain, or increase in the rate of treatment, healing, prevention, inhibition or improvement of such conditions. When applied to an individual active ingredient, which is one that refers to this one ingredient. When applied to a combination, the term refers to the United Koli is the EU ETS active ingredients, which lead to therapeutic effect, regardless of whether they are in combination, sequentially or simultaneously.

Each of the described methods of treatment or use of the present invention includes the introduction of a mammal in need of such treatment, or the use of pharmaceutically or therapeutically effective amount of the compounds of the present invention or its pharmaceutically acceptable salt forms. Compounds of the present invention can be activated by a method according to the invention individually or in combination with other therapies such as treatments employing other anti-inflammatory drugs, cytokines, lymphokines or other hematopoietic factors. At joint application with one or more other anti-inflammatory agents, cytokines, lymphokines or other hematopoietic factors of the compounds of the present invention can be administered simultaneously with other anti-inflammatory(and) drug(s), cytokine(s), lymphokine(s), other hematopoietic(s) factor(s), thrombolytic or antithrombosis means or sequentially. The sequential introduction of the attending physician will decide the appropriate sequence of introducing the compounds of the present invention in combination with other PR is tivovospalitiona(s) drug(s), the cytokine(s), lymphokine(s), other hematopoietic(s) factor(s), thrombolytic or antithrombosis means.

Introduction compounds of the present invention used in the pharmaceutical composition or to practice the method of the present invention, it is possible to carry out a variety of conventional ways, such as oral ingestion, inhalation, or cutaneous, subcutaneous, or intravenous injection.

With the introduction of therapeutically effective amounts of compounds of the present invention by oral compounds of the present invention will be in the form of tablets, capsules, powder, solution or elixir. With the introduction in the form of tablets pharmaceutical composition according to the invention may additionally contain a solid carrier such as gelatin or an adjuvant. Tablet, capsule, and powder contain from about 5 to 95% of the compound of the present invention, and preferably from about 25 to 90% of the compound of the present invention. When introduced in liquid form may be added to the carrier liquid, such as water, petroleum, oils of animal or vegetable nature, such as peanut oil, mineral oil, phospholipids, emulsifiers, triglycerides, including medium chain triglycerides, soybean oil, or sesame oil, or synthetic Massagetae the form of pharmaceutical compositions may further contain physiological saline solution, the solution of dextrose or other saccharide or glycols, such as ethylene glycol, propylene glycol or polyethylene glycol. When introduced in liquid form, the pharmaceutical composition contains from about 0.5 to 90% of the mass of the compounds of the present invention and preferably about 1 to 50% of the compound of the present invention.

When a therapeutically effective amount of the compounds of the present invention is administered by intravenous, cutaneous or subcutaneous injection, the compounds of the present invention will be in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable protein solutions having the proper pH value, isotonicity, stability, etc. known from the prior art. A preferred pharmaceutical composition for intravenous, cutaneous, or subcutaneous injection should contain, in addition to the compounds of the present invention, an isotonic solvent, such as sodium chloride solution for injection, injectable solution, ringer's injection dextrose injection dextrose and sodium chloride, lactate injection ringer's solution or other solvent known in the prior art. The pharmaceutical composition of the present invention may also contain stabilizers, preservatives, buffer substances which STV, antioxidants or other additives known to the expert in this field.

The amount of compound(s) according to the present invention in the pharmaceutical composition of the present invention will depend on the nature and severity of the condition to be treated and on the nature of prior treatments which the patient has undergone. Ultimately the attending physician will decide the amount of the compounds of the present invention, the treatment of each individual patient. Initially, the attending physician will enter a low dose of the compounds of the present invention and to observe the reaction of the patient. A more substantial dose of the compounds of the present invention can be entered until they have been optimal for the patient's therapeutic effect, and at this point the dosage is not increased. It is assumed that the various pharmaceutical compositions used to practice the method according to the present invention should contain about 0.1 μg to 100 mg (preferably from about 0.1 mg to 50 mg, more preferably from about 1 mg to 2 mg) of the compound of the present invention per kg of body weight.

The duration of intravenous therapy using the compositions of the present invention will vary depending on the severity of the disease, which must Le the report, status and potential characteristic response of each individual patient. It is believed that the duration of each application of the compounds of the present invention will be in the range from 12 to 24 hours of continuous intravenous administration. Ultimately the attending physician will decide on the appropriate duration of intravenous therapy using the pharmaceutical compositions of the present invention.

Preferred oral formulations of lipid based on this invention is prepared by mixing 50% PHOSOL®53MCT (American Lecithin Company), 5% Polysorbate 80, 15% of glycerides LABRASOL®Caprylocaproyl macrogol-8 (Gattefosse Corp.), 15% of propylene carbonate and 15% of the active inhibition of cPLA2compound(s) according to this invention, each listed below are the percentage is mass.

This invention also provides a method of preparing compounds according to this invention, which includes one of the following:

a) reaction of compounds of formula A

where X2n, n1n2n3n4,R, R2, R3and R4are as defined in the present description; and R' represents NH2,

with sulphonylchloride formula

halogen-SO2(CH2)n2X1R1,

where halogen represents podhodiashego and n 2X1and R1are as defined in the present description, leading to the corresponding compounds of formula (I),

or

b) hydrolysis of compounds of formula (I), where R2includes ester, resulting in receipt of the appropriate acid,

or

c) the conversion of compounds of formula I having reactive Deputy, into another compound of formula I,

or

d) reaction of compounds of formula A

where X2n, n1n2n3n4,R, R2, R3and R4are as defined in the present description; and

R' represents-NH-S(O)2-(CH2)n2-halogen, or-NH-S(O)2-CH=CH2and n2is the same as defined in the present description,

with a nucleophile of the formula:

HX1R1,

where X1and R1are as defined in the present description, leading to the corresponding compounds of formula (I);

or

e) alkylation of compounds of formula

where R, R1, R3, R4X1and n2are as defined in the present description,

the aldehyde or acetal of the formula

where R2X2and n3are as defined in the present description of the research Institute, or

f) reaction of 3-formylindole formula

where PRT is a protective group, R, R1, R3, R4X1and n2are as defined in the present description,

with an amine of the formula:

RiiiHN-CH2-R2,

where Riiirepresents hydrogen or C1-C3alkyl, and R2is the same as defined in the present description, resulting in obtaining the compounds of formula I, where X2is a-RiiiN-CH2-or

g) reaction of an alkylamine of the formula

where the halogen is a suitable halogen and R, R3and R4are as defined in the present description,

with Alcina formula

where R1, R2X1and X2are as defined in the present description, resulting in a compound of formula (I) or

h) reaction of a halide of the formula

where the halogen is a suitable halogen and R, R2, R3, R4X2n1and n3are as defined in the present description,

with a sulfonamide of the formula

where R1X1and n2are as defined in the present description of the research Institute, leading to the corresponding compounds of formula (I).

This invention also provides intermediate compounds applicable for producing compounds of formula (I), with these intermediate compounds include compounds having the formula (A):

where X2n, n1n2n3n4, R, R2, R3and R4are as defined above; and

R' is selected from the group consisting of-OH, -NH-S(O)2-(CH2)n2-halogen, -NH-S(O)2-CH=CH2, -NH2or a protected form-NH2.

Are examples of intermediate compounds have the formula (B):

where n, n1n2n3n4, R', R, R3and R4are as defined above; and

R8and R9independently selected from H, halogen, -CN, -CHO, -CF3, -OCF3, -OH, -C1-C6of alkyl, -C1-C6alkoxy, -C1-C6thioalkyl, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-(C1-C6alkyl) or-NO2;

R7represents -(CH2)n4-CO2H, ester form -(CH2)n4-CO2H or a pharmaceutically acceptable acid mimic or mimetic connection;

and

X is a linking group selected from the group consisting of-O-, -CH2-, -SO2-, -NH - and-N(C1-C6-alkyl)-.

Preferred intermediate compounds according to this invention includes benzhydrylidene the compounds of formula (C):

where

R', R3, R4, R7-9X, n1n2and n4are as defined above; and

R10, R11, R12, R13, R14and R15independently selected from the group consisting of H, halogen, -CN, -CHO, -CF3, -OCF3, -OH, -C1-C6of alkyl, -C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-(C1-C6alkyl), -NO2or 5 - or 6-membered heterocyclic or heteroaromatic ring containing 1 or 2 heteroatoms selected from O, N or S.

The term "halogen" is used herein to denote F, Cl, Br and I. the Preferred halogen atoms in the R' group-NH-S(O)2-(CH2)n2halogen includes bromine and chlorine.

Preferred ester forms of the compounds of formula C, where R7represents -(CH2)n4-CO2H, are C1-C8alkyl esters, including linear, branched and cyclic alkyl groups, and benzyl esters.

Commercially available and known from the prior techniques is a protective group for an amino group is used to obtain protected forms of the above -(CH 2)n1-NH2groups. Data protective group include groups represented by the following formula, where the number of carbon atoms in the chain are presented only for the purpose of illustration and are not intended to limit the number of carbon atoms in the respective hydrocarbon chains according to this invention.

Other non-limiting examples of protective groups for amino group, used with the compounds according to the invention, include, but are not limited to, the following connections:

1) the amide type, such as formyl, acetyl, chloroacetyl, trichloroacetyl, o-nitrophenylacetic, o-nitrophenoxyacetic, TRIFLUOROACETYL, acetoacetyl, phthalyl and p-toluensulfonyl;

2) aromatic urethane type, such as benzyloxycarbonyl (CBZ) and benzyl substituted one or more times by alkyl, cyano, nitro, chlorine, fluorine, bromine and methoxy; diphenylmethylene, 1-(p-diphenyl)-1-mtilatila, 9-fluorenylmethyl (Fmoc), 2-phenylethylene and cinnamonny group;

3) aliphatic urethane-type, such as tert-butyloxycarbonyl (Boc), ethyl Diisopropylamine, allyl, vinyl, tert-amyl, diisopropylate and isobutyl;

4) cyclic alkyl urethane type, such as cyclopentyl, cyclohexyl, cyclopropylmethyl and substituted;

5) protective alkyl group for an amino group, still is how triphenylmethyl (trityl) and benzyl;

6) trialkylsilyl groups, such as trimethylsilane, triethylsilane, triisopropylsilane, three-tert-butylsilane, triphenylsilane, tricalysia, trimethylarsine, methyldiphenylamine, disaffirmation, bis(diphenyl)methylsilane etc.; and

7) protective group containing a thiol, such as phenylthiocarbamyl and dithiazole protective group.

Other preferred protective groups for the amino group, are applicable in this invention are ethoxycarbonyl groups, acyl groups, including 4-chlorobutyryl, isobutyryl, nitrocinnamyl, pikolinos, utilizationand, aminocaproyl, benzoyl and similar, and alloctype, including methoxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-cryptgetuserkey, 2-trimethylsilylethynyl, vinyloxycarbonyl, allyloxycarbonyl, 1,1-dimethylphenylcarbinol, p-nitrobenzenesulfonyl, 2,4-dichlorobenzenesulfonyl and similar.

Pharmaceutically acceptable acid mimic or mimetic compounds that can be attached in position R7include compounds of the formulas:

where Rachosen from-CF3, -CH3, phenyl or benzyl, with the phenyl or benzyl group optionally substituted by 1-3 groups selected from-C1-C6Alki is a, -C1-C6alkoxy, -C1-C6thioalkyl, -CF3, halogen, -OH or-COOH; Rbchosen from-CF3, -CH3, -NH2, phenyl or benzyl, with the phenyl or benzyl group optionally substituted by 1-3 groups selected from-C1-C6of alkyl, -C1-C6alkoxy, -C1-C6thioalkyl, -CF3, halogen, -OH or-COOH; and Rcchosen from-CF3or-C1-C6the alkyl.

Other preferred compounds of this invention represented by the formula D:

where each of the variables R3, R4, R8-R15X and n4 are as defined above. Especially preferred are the compounds of formula (D), in which R10-R15represent hydrogen.

Another preferred intermediate compounds according to the invention are the compounds of formula E

where each of the variables R3-R15and X are as defined above.

Especially preferred practice of this invention are the compounds of formula E in which R10-R15represent hydrogen.

Among the most preferred intermediate compounds of the present invention are carried away the lower connection named intermediate compounds No. 1, 2 and 3. Also shown illustrating the method of obtaining these compounds. These examples of particularly preferred compounds and methods should not be construed as limiting the scope of the invention.

The production of intermediate compounds is illustrated below.

The intermediate connection # 1

Methyl ester of 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]econsultancy}benzoic acid

Stage 1:2-Bromo-4-Chloroaniline (1.0 EQ.) dissolved in CH2Cl2(0.25 M), then add triethylamine and triperoxonane anhydride (1.1 EQ. each). The resulting mixture was stirred at room temperature for 1 hour. Then from the reaction mixture to remove the solvent and the residue purified flash chromatography with dichloromethane as eluent, obtaining the desired product with a yield of 97%. m/z(M-H)-300,0.

Stage 2:N-(2-bromo-4-chlorophenyl)-2,2,2-triptorelin (stage 1, 1.0 EQ.) mix with 3-buten-1-ol (2.0 equiv.) dichlorobis(triphenylphosphine)palladium(II) (2.5% equiv.) by triethylamine (3.0 EQ.), CuI (5% equiv.) in DMF (0.2 M) in a sealed vessel in an atmosphere of N2and heat at 120°C for 4 hours. Then the reaction mixture was diluted with ethyl acetate, washed with saturated salt solution and dried over Na2SO 4. Next, the solvent is evaporated and the residue purified column flash chromatography using a mixture of 2% MeOH/CH2Cl2getting described 2-(5-chloro-1H-indol-2-yl)ethanol with a yield of 67%. m/z (M-H)-194,09.

Stage 3: 2-(5-chloro-1H-indol-2-yl)ethanol (1 EQ.) add to the solution (under the N2containingtert-butyldiphenylchlorosilane (1.2 equiv.) the imidazole (2.5 EQ.) and DMF (1.8 M). The reaction mixture was stirred over night. Quenched with NaHCO3(aq.)and extracted with a mixture of Et2O/EtOAc. The organic layer is washed with water, saturated salt solution and dried over sodium sulfate. Purified on a column of silica gel and as eluent a mixture of 1:4 hexane/CH2Cl2. Get 2-({[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indole (yellow oily substance) with the release of 98%.

Stage 4: To a solution containing 2-({[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indole (1 EQ.), TFU (3 EQ.) and 1,2-dichloroethane (0.1 M)at 0°C in an atmosphere of N2add methyl 4-[(2-oxoethyl)sulfanyl]benzoate (3.7 EQ.). Then add Et3SiH (12 equiv.) the reaction mixture is allowed to warm to room temperature and stirred over night. The reaction mixture was quenched with NaHCO3(aq.), extracted with EtOAc, washed with saturated salt solution and dried over sodium sulfate. Purified on a column of silica gel and kachestvenna use a mixture of 1:5 EtOAc/hexane. Obtain methyl 4-({2-[2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfanyl)benzoate (solid yellow substance) with the release of 79%.

Stage 5: To a suspension of NaH (1.1 EQ.) in DMF (0,37 M) at 0°C in an atmosphere of N2add methyl 4-({2-[2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfanyl)benzoate (1 EQ.). After 30 minutes, add Ph2CHBr (1.8 EQ.) and the reaction mixture is heated to room temperature. After 3 hours the reaction mixture was quenched with NH4Cl(aq.), extracted with a mixture of EtOAc/Et2O, washed with water, saturated salt solution and dried over sodium sulfate. Purified on a column of silica gel and as eluent a mixture of 1:5 EtOAc/hexane. Obtain methyl 3-[4-({2-[1-benzhydryl-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (yellow resinous substance) with the release of 65%.

Stage 6:To a solution/suspension containing methyl 3-[4-({2-[1-benzhydryl-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (1 EQ.), Acrylonitrile (0.1 M) and molecular sieves (1 g/mmol benzoate), in an atmosphere of N2added NMO (4 EQ.). After 10 minutes add TPAP (0,12 EQ.) and the mixture is heated to 40°C. After 1.5 hours the reaction mixture is cooled, filtered and collect the filtrate. Purified on a column of silica gel with use of the mixture of 1:5 EtOAc/hexane. Obtain methyl 3-[4-({2-[1-benzhydryl-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (white solid) with a yield of 71%.

Step 7: To a solution of methyl 3-[4-({2-[1-benzhydryl-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (1 EQ.) and THF (0.1 M) at 0°C in an atmosphere of N2add tetrabutylammonium fluoride (1M in THF) (1.2 EQ.). The reaction mixture is heated to room temperature and after 1 hour and quenched with NH4Cl(aq.). Extracted with EtOAc, washed with saturated salt solution and dried over sodium sulfate. Purified on a column of silica gel using a mixture of 1:9 EtOAc/CH2Cl2. Obtain methyl 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (white solid) with a yield of 86%.

Stage 8:To a solution of methyl 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (1 EQ.) in CH2Cl2(0.02 M) at 0°C in an atmosphere of N2add CH3SO2Cl (2 EQ.) and Et3N (2.5 EQ.). After 1 hour the reaction mixture is heated to room temperature. After an additional hour, add water and extracted with CH2Cl2, washed with saturated salt solution and dried over sodium sulfate. Remove the solvent to obtain methyl 3-(4-{[2-(1-benzhydryl-chlor-2-{2-[(methylsulphonyl)oxy]ethyl}-1H-indol-3-yl)ethyl]sulfonyl}phenyl)benzoate (solid light yellow substance) with a yield of 99%.

Stage 9:Methyl 3-(4-{[2-(1-benzhydryl-5-chloro-2-{2-[(methylsulphonyl)oxy]ethyl}-1H-indol-3-yl)ethyl]sulfonyl}phenyl)benzoate (1 EQ.), sodium azide (5 EQ.) and DMF (0.05 M) is mixed in an atmosphere of N2and heated to 60°C. After 1 hour the reaction mixture is cooled and water is added. Extracted with a mixture of EtOAc/Et2O, washed with water, saturated salt solution and dried over sodium sulfate. Remove the solvent, obtaining methyl 3-[4-({2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (solid light yellow substance) with a yield of 99%.

Step 10: Methyl 3-[4-({2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (1 EQ.), PPh3(2 EQ.) and THF (0.1 M) is mixed in an atmosphere of N2and stirred over night. Add water (1 ml/1 mmol benzoate) and the reaction mixture is again stirred overnight. The solution is concentrated and purified on a column of silica gel using a mixture of 3:1 EtOAc/hexane, then 5% MeOH in CH2Cl2. Obtain methyl 3-[4-({2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (solid light yellow substance) with a yield of 99%.

Synthesis of intermediate compound No. 1 as described below in example 135, stages 1-8. This intermediate compound can also be synthesized by a method or by a method M, which are explained below.

The intermediate connection # 2

Methyl ester of 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1Hindol-3-yl]ethoxy}benzoic acid

Stage 1:To the methyl ester of 4-hydroxybenzoic acid (1.0 EQ.) in DMF (0,83 M) add K2CO3(2.0 equiv.) then add 2-bromo-1,1-diethoxyethane and the reaction mixture is stirred at 110°C for 2 days. TLC shows the new spot. The reaction mixture was diluted with ethyl acetate, washed with 1 N. NaOH, water, saturated salt solution, dried over sodium sulfate and the solvent is removed, obtaining the desired product with a yield of 84%. This substance is used in the next stage without additional purification.

Stage 2:To the mixture obtained in the previous stage of the product (1.0 EQ.) and 5-chloro-2-methylindole (1.0 EQ.) in CH2Cl2(0.12 M) add triethylsilane (3.0 equiv.) then add triperoxonane acid (3.0 EQ.). After stirring overnight at room temperature to the reaction mixture, water is added and triperoxonane acid (1 EQ.), stirred at room temperature for 2 days, diluted with CH2Cl2, washed with 1 N. NaOH, water, saturated salt solution and dried over sodium sulfate. The grinding substances in a mixture of CH2Cl2and hexane gives C3 alkilirovanny indole with the release of 92%.

Stage 3: To the indole from the previous article is Hai (1.0 EQ.) in DMF (0.36 M) at 25° With added NaH (1.2 EQ., 60% dispersion in oil) and the brown solution is stirred at a temperature of from 0 to -5°C for 1 hour, then add bromodiphenylmethane (1.1 EQ.) and then the reaction mixture was stirred over night. Then it is quenched with water, diluted with ethyl acetate, washed with water, saturated salt solution, dried over sodium sulfate and purified column chromatography, obtaining the desired product with a yield of 72%.

Stage 4:To N-alkilirovannami the indole from the previous stage (1.0 EQ.) in CCl4(0.2 M) is added N-bromosuccinimide (2.0 EQ.) and a catalytic amount of benzoyl peroxide. The solution is refluxed for 3 h, cooled to 25°C, filtered and the solid is washed with CCl4. The filtrate is concentrated to a foam, which is dried. The foam was dissolved in acetone and added Ag2CO3(1.1 equiv.) then water is added and the reaction mixture was stirred over night at room temperature. The mixture is filtered and washed with acetone. The filtrate is concentrated to a residue, to which water is added. This mixture is extracted with ethyl acetate, washed with saturated salt solution, dried over sodium sulfate, and then the chromatographic purification of the residue gives the desired product with a yield of 85%. Alternative dibromide from the reaction with N-bromosuccinimide you can pour in DMSO (10-20% concentration of pomace), stirring for 30 minutes at room temperature. After completion of the reaction, the reaction mixture was poured into water and the resulting precipitate was separated by filtration, the filter cake washed with water and dried, obtaining essentially quantitative yield.

Stage 5:The aldehyde from the previous step (1.0 EQ.) in CH3NO2(0.2 M) is added ammonium acetate (4 equiv.) and the resulting mixture is refluxed for 4 hours. Then the reaction mixture was diluted with EtOAc and washed with a saturated solution of salt. The aqueous phase is extracted with EtOAc. The combined organic phases are washed with saturated salt solution, dried over sodium sulfate and concentrated until precipitation of a solid orange crystalline substance. The mixture is cooled overnight and filtered to collect nitroolefins (yield 76%). The evaporation phase of the solvent and purification of the residue column chromatography (gradient elution 100% toluene→1% EtOAc-toluene) gives more nitroolefins (yield 23%).

Stage 6:Zinc dust (20 EQ.) suspended in 5% aqueous HCl solution (8 M Zn/5% HCl). To this mixture add HgCl2(0,28 EQ.). The mixture was shaken for 10 min, the aqueous phase is decanted and replaced with fresh 5% HCl, the mixture is again shaken for 5 min and the aqueous phase is removed. Then thus obtained and is the Alhama zinc-mercury added to a mixture of nitroolefins (1.0 EQ.) and concentrated HCl (80 EQ.) in THF (0.04 M of nitroolefins/THF). The mixture is subjected to mild boiling under reflux for 1 hour. For the formation of the product watch TLC. The mixture is cooled to room temperature and the solid removed by filtration through celite. To the phase of the solution was added concentrated NH4OH and the mixture concentrated on a rotary evaporator. The residue is dissolved in CH2Cl2and concentrated NH4OH. The aqueous phase is extracted with CH2Cl2and the organic phase is washed with saturated salt solution, dried over sodium sulfate and concentrated. Purification of column chromatography gives the desired product (yield 65%).

Synthesis of intermediate compound No. 2 is also described in example 1, stages 1-6. This intermediate compound can also be synthesized using the methods of the K, L or M, as set forth below.

The intermediate connection # 3

Methyl ester of 4-{3-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1Hindol-3-yl]propyl}benzoic acid

Stage 1:A mixture of methyl-4-identity (5.3g, a 20.2 mmol), allyl alcohol (1.78 g, 30.3 mmol), NaHCO3(4,24 g, and 50.5 mmol), Pd(OAc)2(0.14 g, of 0.60 mmol), (n-Bu)4NBr (6,55 g, a 20.2 mmol) and molecular sieves 4 Å (4.1 g) in anhydrous DMF (69 ml) was stirred at room temperature for 4 days. The reaction mixture was filtered through celite, the filtrate was poured into water and the ex is reginout EtOAc. The organic layer was washed with saturated salt solution, dried (Na2SO4) and concentrated in vacuo. Flash chromatography (silica gel, 10-20% EtOAc-hexane) gives 2,11 g (85% based on the recovered original substance) of the desired methyl ester 4-(3-oxopropyl)benzoic acid as a transparent oily substance.

Stage 2:To a solution of 5-chloro-2-methylindole (0,86 g, 5.2 mmol) and methyl ester of 4-(3-oxopropyl)benzoic acid (1.0 g, 5.2 mmol) in methylene chloride (50 ml) is added TFU (1.78 g, 15.6 mmol), and then add triethylsilane (1,81 g, 15.6 mmol). The reaction mixture was stirred overnight, quenched with saturated solution of NaHCO3(50 ml) and the organic layer was washed with a saturated solution of NaHCO3, water, saturated salt solution and dried (Na2SO4). The solvent is removed under reduced pressure and the residue purified column flash chromatography using a mixture of 10-20% EtOAc/hexane, obtaining the desired product with a yield of 94% (1,67 g).

Stage 3:To the solution obtained in stage 2 product (1.66 g, a 4.86 mmol) in DMF (20 ml) is added NaH (60% in mineral oil, 0.24 g, 5.83 mmol) in an atmosphere of N2. The mixture is stirred for 1 hour at room temperature, then added dropwise to benzhydrylamine (1.8 g, 7,29 mmol) in DMF (5 ml). This reaction mixture is stirred over night at room temp is the temperature. To the reaction mixture are added water (500 ml), extracted with EtOAc, washed with saturated salt solution, dried (Na2SO4) and concentrate under reduced pressure to a brown syrup, which was purified by chromatography on silica gel using a mixture of 10% EtOAc/hexane as eluent, getting 4 in the form of a white solid with a yield of 59% (1.47 g).

Stage 4:The product from the previous stage (1,46 g, 2,87 mmol) dissolved in CCl4(14,5 ml), then add N-bromosuccinimide (1,02 g, 5,73 mmol) and benzoyl peroxide (2 mg). The reaction mixture is refluxed for 1 hour (until you disappear all the original substance). This mixture is cooled to room temperature, filtered and the solid is washed with CCl4. The filtrate is evaporated to a brown residue, which was dissolved in acetone (40 ml) and water (4 ml), then to this solution was added Ag2CO3(1,75 g, and 3.16 mmol) and after stirring over night at room temperature the solution is filtered through celite, the solvent is evaporated under reduced pressure and to the residue water is added. This mixture is extracted with EtOAc, washed with saturated salt solution, dried (Na2SO4) and evaporated to a syrup, which is cleaned with a mixture of 10% EtOAc/hexane, allocating 2-formylindole (1.13 g) with a yield of 75%. Alternative dibromide from the reaction with N-bromosuccinimide can is elite in DMSO (10-20% concentration by weight) and stir for 30 minutes at room temperature. After completion of the reaction, the reaction mixture was poured into water and the resulting precipitate was separated by filtration, the filter cake washed with water and dried, obtaining essentially quantitative yield.

Stage 5:To a solution of 2-formylindole from the previous stage (0.52 g, 1 mmol) in CH3NO2(6.2 ml) is added NH4OAc (0,077 g, 1 mmol), the mixture is refluxed for 1 h, then add NH4OAc (0,077 g, 1 mmol), continue to boil under reflux for an additional 1 h, again add NH4OAc (0,077 g, 1 mmol) and continue heating for an additional 1 hour. The reaction mixture is cooled to room temperature, add EtOAc (50 ml), then add 100 ml of water. The aqueous layer was extracted with EtOAc and the combined organic layers washed with saturated salt solution, dried (Na2SO4) and evaporated to education yellow foam, which is subjected to chromatographic purification using a mixture of 10% EtOAc/hexane as eluent, getting 6 as a yellow foam with a yield of 68% (range 0.38 g).

Stage 6:Get Zn(Hg), adding HgCl2(3.4 g, 7.2 mmol) to a mixture of zinc dust (34,68 g, 530,35 mmol) and 5% HCl (38 ml) in a 100 ml flask and intensively stirring this mixture for 10 minutes the Aqueous phase is decanted, again add 38 ml of 5% HCl and the mixture is stirred for 10 minutes the Aqueous phase de is antiroot. This solid is added to the vinyl nitrosoaniline 6 (15 g, 26,57 mmol) in THF (660 ml) and concentrated HCl (64,5 ml). This mixture is stirred at room temperature for 1 h, and then refluxed for 15 minutes, the Reaction mixture was cooled to room temperature and filtered through celite. To the filtrate is added an aqueous solution of NH4OH (200 ml), stirred for 15 min and remove the THF under reduced pressure. The aqueous layer was extracted with CH2Cl2combined organic layer was washed with saturated salt solution, dried (Na2SO4) and concentrated to a brown foam, which is purified column chromatography, first elwira column CHCl3to remove non-polar impurities, then with a mixture of 2% MeOH/CHCl3to select the desired amine to yield 46% (6,1 g).

Synthesis of intermediate compound No. 3 is also described below in example 42, stages 1-6. This intermediate compound can also be obtained using the methods of J, K or M, as set forth below.

The intermediate connection # 4

Methyl ester of 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1Hindol-3-yl]ethylamino}benzoic acid

Stage 1:To a solution of 4-chloro-2-joanina (16.5 g, a total of 65.1 mmol) in DMF (250 ml) at room temperature add α-bromodiphenylmethane (21,5 g,and 84.6 mmol) and fromPr2NEt (23 ml, 130 mmol) and the reaction mixture is heated at 45°With during the night. After removal of volatiles under reduced pressure the residue is dissolved in EtOAc, washed with water (3×), saturated salt solution and dried over MgSO4. Purification of column chromatography on SiO2(from hexanol to a mixture of 5% EtOAc/hexane) gives the desired benzhydryl-(4-chloro-2-itfinal)Amin (26,1 g, yield 97%) as a yellowish solid substance.

Stage 2:The mixture benzhydryl-(4-chloro-2-itfinal)amine (26,1 g, 62,2 mmol), PdCl2(PPh3)2(1.90 g, to 2.67 mmol), CuI (1.2 g, 6.2 mmol), 3-buten-1-ol and Et3N (120 ml) was stirred at 45°C for 20 hours. The reaction mixture was filtered through celite and washed with EtOAc. The filtrate is concentrated and re-dissolved in EtOAc, washed with water (3×) and saturated salt solution and dried over MgSO4. The crude 4-[2-(benzylamino)-5-chlorophenyl]but-3-in-1-ol (25,5 g) used directly in the next stage without additional purification.

Stage 3:A solution of the crude 4-[2-(benzylamino)-5-chlorophenyl]but-3-in-1-ol (25,5 g) and CuI (2.7 g, 14.1 mmol) in DMF (200 ml) is heated at 125°C for 24 hours. The reaction mixture was filtered through celite and washed with EtOAc. The filtrate is concentrated and re-dissolved in EtOAc, washed with water (3×), saturated salt solution and dried over MgSO4. Column chrome is tography on silica gel (30% EtOAc/hexane) gives the desired 2-(1-benzhydryl-5-chloro-1H-indol-2-yl)ethanol in the form of a yellow solid substance (14.5 g, 73% over 2 stages).

Stage 4: To a solution of 2-(1-benzhydryl-5-chloro-1H-indol-2-yl)ethanol (15.3 g, of 42.3 mmol) in CH2Cl2(190 ml) at 0°With add imidazole (3,72 g, 55,0 mmol) and TBDPSCl (13,2 ml, 50.8 mmol). After stirring at the same temperature for 1.5 hours the reaction mixture is washed with cold water (3×), saturated salt solution and dried over MgSO4. The crude silyl ether directly used in the next stage without additional purification.

Stage 5: To a solution of the crude silyl ether in Et2O (200 ml) at 0°With added dropwise oxalicacid (4,84 ml of 55.5 mmol). The reaction mixture is allowed to warm to room temperature and stirring is continued for 4 hours, then add Et3N (35 ml) and MeOH (10 ml). The mixture is washed with water, saturated salt solution and dried over MgSO4. Raw ketoester directly used in the next stage.

Stage 6: metafire in THF (300 ml) dropwise at room temperature add BH3·Me2S (10 M, 36 ml) and the reaction mixture refluxed overnight. The mixture is cooled to 0°With, then add NaOH (30%, 150 ml) and stirring continued for 30 minutes Under reduced pressure to remove THF and the reaction mixture is extracted with EtOAc, washed with water, saturated salt solution and dried over MgSO4

Step 7: To a solution of oxalicacid (0,372 ml, 4,27 mmol) in CH2Cl2(10 ml) at -78°With added dropwise DMSO (0,661 ml, 9,31 mmol). The reaction mixture was stirred at the same temperature for 5 minutes, then add a solution of 2-{1-benzhydryl-2-[2-(tert-butyldiphenylsilyl)ethyl]-5-chloro-1H-indol-3-yl}ethanol (2.50 g, 3.88 mmol) in CH2Cl2(8 ml). After an additional 40 min stirringiPr2NEt (3,38 ml of 19.4 mmol), the reaction mixture is quenched with cold water (5 ml) and extracted with CH2Cl2. The organic layer is dried over MgSO4and evaporated. The crude {1-benzhydryl-2-[2-(tert-butyldiphenylsilyl)ethyl]-5-chloro-1H-indol-3-yl}acetaldehyde directly used in the next stage.

Step 8: To a solution of the crude aldehyde (3.88 mmol) in 1,2-dichloroethane (39 ml) at 0°With added methyl 4-aminobenzoate (645 mg, 4,27 mmol), acetic acid (1,33 ml) and NaBH(OAc)3. The reaction mixture is allowed to warm to room temperature overnight and quenched with cold NaHCO3. Extractive processing will give the desired methyl ester 4-(2-{1-benzhydryl-2-[2-(tert-butyldiphenylsilyl)ethyl]-5-chloro-1H-indol-3-yl}ethylamino)benzoic acid, which is not orestano use in the next stage without additional purification.

Step 9: methyl ether of 4-(2-{1-benzhydryl-2-[2-(tert-butyldiphenylsilyl)ethyl]-5-chloro-1H-indol-3-yl}ethylamino)benzoic acid (3.88 mmol) in THF (25 ml) at 0°add the mixture of HOAc:1M TBAF (in THF) (2,3 ml:5.8 ml) and the reaction mixture was stirred at room temperature for 18 hours. Extractive processing, followed by rubbing in a mixture of 5% EtOAc/hexane to give the desired methyl ester 4-{2-[1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethylamino}benzoic acid, with a small admixture, in the form of a solid off-white substance (92% for stage 3).

Step 10: To a solution of methyl ester 4-{2-[1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethylamino}benzoic acid (1.64 g, 3.04 from mmol) in CH2Cl2when 0°add Et3N (0,636 ml, 4,56 mmol) and MsCl (0,282 ml of 3.64 mmol). After stirring at the same temperature for 35 min, the reaction mixture was quenched with cold water. Extractive processing gives the crude mesilate in the form of a solid off-white substance (1.70 g, 90%).

Stage 11: a Solution of the crude nelfinavir (1.70 g, a 2.75 mmol) and NaN3(89 mg, of 13.8 mmol) in DMF (14 ml) was stirred at 80°C for 6 hours. The reaction mixture was diluted with EtOAc and treated with water, followed by column flash chromatography, obtaining the desired methyl ester 4-{2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethylamino}benzoic what Islami (813 mg, yield 52%).

Step 12: To a solution of methyl ester 4-{2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethylamino}benzoic acid (400 mg, 0,709 mmol) in THF (4 ml) at 0°With the parts add Ph3P (223 mg, 0,851 mmol). The reaction mixture was stirred at room temperature for 11 hours and 35°C for 4 h, after which water is added (50 μl) and stirring is continued over night. The reaction mixture was diluted with EtOAc, dried with MgSO4and clear column flash chromatography (EtOAc to 20% MeOH/EtOAc with 1% Et3N), obtaining the desired methyl ester 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethylamino}benzoic acid (201 mg, 53%) as a solid.

Synthesis of intermediate compound No. 4 is also described below in example 142, the stage 1-12.

The intermediate connection # 5

Methyl ester of 4-({2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1Hindol-3-yl]ethyl}methylamino)benzoic acid

Stage 1:The crude {1-benzhydryl-2-[2-(tert-butyldiphenylsilyl)ethyl]-5-chloro-1H-indol-3-yl}acetaldehyde synthesis of intermediate compound No. 4, stage 7 is treated with methyl ether 4-methylaminoethanol acid by the procedure described in the synthesis of intermediate compound No. 4, stage 8, receiving the desired methyl ester 4-[(2-{1-benzhydryl-2-[2-(tert-butyldiphenylsilyl)ethyl]-chlor-1H-indol-3-yl}ethyl)methylamino]benzoic acid with a yield of 73%.

Stage 2:Specified in the header connection get the procedure described for intermediate connection No. 4, stage 9. The crude methyl ester of 4-({2-[1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethyl}methylamino)benzoic acid directly used in the next stage without additional purification.

Stage 3-6: Methyl ester of 4-({2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}methylamino}benzoic acid obtained by the procedure described for intermediate connection No. 4, stage 10-12, exit 61% (for stage 3).

Step 7: a Solution of methyl ester 4-({2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}methylamino}benzoic acid (410 mg, 0,709 mmol) and 10% Pd/C (155 mg) in MeOH:CH2Cl2(7 ml:1 ml) is stirred in an atmosphere of H2(1 ATM) for 2 hours 15 minutes the Reaction mixture was filtered through celite and washed with MeOH and CH2Cl2. Column flash chromatography of the residue (CH2Cl2up to 8% MeOH/CH2Cl2) gives the desired methyl ester of 4-({2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}methylamino)benzoic acid with a yield of 78% (305 mg).

Synthesis of intermediate compound No. 5 is also described below in example 146, stages 1-7.

Compounds according to this invention can be used as intermediates in the synthesis of pharmaceutically applicable compounds of formula I, VK is UCA connection which have the formula IA:

where

X is a linking group selected from-O-, -CH2-, -SO2-, -NH - and-N(C1-C6alkyl)-;

R10, R11, R12, R13, R14and R15independently selected from H, halogen, -CN, -CHO, -CF3, -OCF3, -OH, -C1-C6of alkyl, -C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-(C1-C6alkyl), -NO2or 5 - or 6-membered heterocyclic or heteroaromatic ring containing 1 or 2 heteroatoms selected from O, N or S;

R8and R9independently selected from H, halogen, -CN, -CHO, -CF3, -OCF3, -OH, -C1-C6of alkyl, -C1-C6alkoxy, -C1-C6thioalkyl, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-(C1-C6alkyl) or-NO2;

R7is a compound of the formula -(CH2)n4-CO2H or a pharmaceutically acceptable acid mimic or mimetic compound, as defined above;

R3and R4are as defined above;

n1an integer from 1 to 3;

n2an integer from 0 to 4;

X1selected from a chemical bond, -S-, -O-, -S(O)-, -S(O)2-, -NH-, -NHC(O)-, -C=C-,

R16represents a cyclic group selected from C1-C6alkyl, C1-C6fluorinated alkyl, C3-C6cycloalkyl, tetrahydropyranyl, campaniles, Adamantine, CN, -N(C1-C6alkyl)2, phenyl, pyridinoline, pyrimidinyl, furillo, thienyl, naftilos, morpholinyl, triazoline, pyrazolidine, piperidinyloxy, pyrrolidinyloxy, imidazolidine, piperazinilnom, thiazolidinones, thiomorpholine, tetrazole, indole, benzoxazole, benzofuranol, imidazolidin-2-tikovoi, 7,7-dimethylbicyclo[2.2.1]heptane-2-about or pyrrolidino groups, each of which is optionally substituted 1-3, preferably 1-2 substituents, independently selected from H, halogen, -CN, -CHO, -CF3, -OH, -C1-C6of alkyl, -C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-(C1-C6alkyl), -NO2, -SO2(C1-C3alkyl), -SO2NH2, -SO2NH(C1-C3alkyl), -SO2N(C1-C3alkyl)2, -OCF3, -COOH, -CH2-COOH, -CH2-N(C1-C6alkyl), -CH2-N(C1-C6alkyl)2, -CH2-NH2, pyridine or

or their pharmaceutically acceptable salt and the ester and forms.

Among the more preferred ester forms of the compounds of formula (IA), where R7has the formula -(CH2)n4-CO2H, are C1-C8alkyl esters, including linear, branched, or cyclic alkyl group, or benzyl esters.

Compounds according to the invention can be prepared by any method described here. Where necessary, reactive fragments or sections for the reaction can be protected with suitable protective agents, which are removed after completion of the reaction. Suitable reagents are well known in the prior art.

The compounds of formula I can be prepared by a method including the interaction of the compounds of formula A, where R' represents NH2with sulphonylchloride formula halogen-SO2(CH2)n2X1R1where the halogen is a suitable halogen, for example Cl, and n2X1and R1are as defined in the present description. It can accordingly be carried out at two-phase conditions, for example using a mixture of aqueous sodium bicarbonate/dichloromethane, or in an organic solvent with addition of a blocked organic amine base.

The compounds of formula I can also be prepared by a process comprising the hydrolysis of compounds of formula I, where R2on what he hopes ester, in order to provide the corresponding acid. It can accordingly be carried out if the basic conditions with sodium hydroxide in water, methanol and THF at room temperature or at elevated temperature. Alternative cleavage can respectively hold processing thiamethoxam sodium in a solvent such as THF or DMF, at elevated temperature (for example, 50°S-100°).

The compounds of formula I can also be prepared by a process comprising converting the compounds of formula I having reactive Deputy, into another compound of formula I. for Example, the halogen can be converted into the corresponding amine. It can accordingly be carried out using a base, amine, phosphine ligand and a palladium reagent.

The compounds of formula I can also be prepared by a method including the interaction of the compounds of formula A, where R' represents-NH-S(O)2-(CH2)n2-halogen, or-NH-S(O)2CH=CH2and n2is the same as defined in the present description, with a nucleophile of the formula HX1R1where X1and R1are as defined in the present description. It can accordingly be carried out using a suitable organic base such as Hunigs base, and heating to complete the reaction.

The compounds of formula I can also when is otavite way including the alkylation of compounds of formula

where R, R1, R3, R4X1and n2are as defined in the present description,

the aldehyde or acetal of the formula

where R2X2and n3are as defined in the present description.

It can accordingly be carried out under the action of acids Bronsted or Lewis, such as triperoxonane acid, and a reducing agent, such as triethylsilane.

The compounds of formula I, where X2is a-RiiiN-CH2-can be prepared by a process involving the interaction of 3-formylindole formula

where PRT is a protective group, R, R1, R3, R4X1and n2are as defined in the present description, with an amine of formula RiiiHN-CH2-R2-, where Riiirepresents hydrogen or C1-C3alkyl, and R2is the same as defined in the present description.

This procedure can accordingly be implemented in a mixture of reducing agent, such as triacetoxyborohydride sodium, and acid, such as glacial acetic acid. Suitable protective groups are well known in the prior art.

The compounds of formula I can also p is gotovit way including the interaction of the alkylamine of the formula

where the halogen is a suitable halogen, such as I or Br, and R, R3and R4are as defined in the present description,

with Alcina formula

where R1, R2X1and X2are as defined in the present description.

This procedure can accordingly be carried out using palladium as a catalyst in the presence of a source of chloride, the base and in the presence or in the absence of phosphine.

The compounds of formula I can also be prepared by a method including the interaction of the halide of the formula

where the halogen is a suitable halogen such as Br, and R, R2, R3, R4X2and n3are as defined in the present description,

with a sulfonamide of the formula

where R1X1and n2are as defined in the present description.

This procedure can accordingly be carried out using a strong base, such as NaH, n-butyl-Li, etc.

This invention can be further explained by the following non-limiting specific examples illustrating the receive connections from the retenu.

Method A

Source indole method A can be alkilirovanii in C3 position (the carbon atom at the 3-position of the indole group) aldehydes or the corresponding acetals in the presence of a Lewis acid or Bronsted, such as athirat of boron TRIFLUORIDE or triperoxonane acid. Then the indole nitrogen can be alkilirovanii processing strong base, such as sodium bis(trimethylsilyl)amide, n-butyl-Li, sodium hydride or potassium hydride, in a solvent such as DMF, DMSO or THF, followed by interaction with a corresponding alkylhalogenide. The resulting product can be processed cetarehhloristam carbon in carbon tetrachloride and a catalytic amount of benzoyl peroxide to make dibromononane C2 methyl group. Then dibromide can be mixed with silver carbonate in a mixture of acetone and water or pour in DMSO and mix. Both these procedures give the aldehyde, which is then subjected nitroaldol reaction with nitromethane and a catalytic amount of ammonium acetate by boiling under reflux. The resulting intermediate vinyl nitrosoaniline reduced to amine by treatment with zinc-mercury amalgam in a mixture of THF and concentrated HCl while boiling under reflux. This amine is ATEM can handle the necessary sulphonylchloride for two-phase conditions, in a mixture of an aqueous solution of sodium bicarbonate/dichloromethane, or in an organic solvent with addition of a blocked organic amine base. The final hydrolysis perform under basic conditions with sodium hydroxide in water, methanol and THF at room temperature or at elevated temperature. Alternative cleavage can be accomplished by treatment with thiamethoxam sodium in a solvent such as THF or DMF, at elevated temperature (50°S-100°). This method is used in the syntheses of examples 1-88, 108-112 and 126-128.

Method In

Method B

Source halide method B is refluxed in an aqueous solution of sodium sulfite and a suitable co-solvent, if necessary, such as alcohol, dioxane, etc. in the time required to give the desired sulfonate sodium. This intermediate compound is treated with thionyl chloride, pentachloride phosphorus or oxalylamino in dichloromethane with a small amount of DMF and stirred for several hours at room temperature to obtain sulphonylchloride. Thus obtained sulphonylchloride then use the crude method A. This method is used in the synthesis of examples 1-88, 108-112 and 126-128, when sulphonylchloride is not commercially available.

<> Example 1:4-[2-(1-benzhydryl-2-{2-[(benzylmethyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoic acid

This synthesis is described in method A.

Stage 1: To the methyl ether of 4-hydroxybenzoic acid (1.0 EQ.) in DMF (0,83 M) add K2CO3(2.0 equiv.) then add 2-bromo-1,1-diethoxyethane and the reaction mixture is stirred at 110°C for 2 days. TLC shows the new spot. The reaction mixture was diluted with ethyl acetate, washed with 1 N. NaOH, water and saturated salt solution, dried over sodium sulfate and the solvent is removed, obtaining the desired product with a yield of 84%. This material is used in the next stage without additional purification.

Stage 2: To the product from the previous step (1.0 EQ.) and 5-chloro-2-methylindole (1.0 EQ.) in CH2Cl2(0.12 M) add triethylsilane (3.0 equiv.) then add triperoxonane acid (3.0 EQ.). After stirring overnight at room temperature to the reaction mixture, water is added and triperoxonane acid (1.0 EQ.), stirred at room temperature for two days, diluted with CH2Cl2, washed with 1 N. NaOH, water, saturated salt solution and dried over sodium sulfate. The grinding substances in a mixture of CH2Cl2and hexanol gives C3 alkilirovanny indole with the release of 92%.

Stage 3: In the indole from the previous step(1.0 EQ.) in DMF (0.36 M) at 25° With added NaH (1.2 EQ., 60% dispersion in oil) and the brown solution is stirred at a temperature of from 0 to -5°C for 1 hour, then add the connection bromodiphenylmethane (1.1 EQ.) and then the reaction mixture was stirred over night. Then it is quenched with water, diluted with ethyl acetate, washed with water and saturated salt solution, dried over sodium sulfate and purified column chromatography, obtaining the desired product with a yield of 72%.

Stage 4: N-alkilirovannami the indole from the previous step (1.0 EQ.) in CCl4(0.2 M) is added N-bromosuccinimide (2.0 EQ.) and a catalytic amount of benzoyl peroxide. The solution is refluxed for 3 hours, cooled to 25°C, filtered and the solid is washed with CCl4. The filtrate is concentrated to a foam, which is dried. The foam was dissolved in acetone and added Ag2CO3(1.1 equiv.) then water is added and the reaction mixture was stirred over night at room temperature. The reaction mixture was filtered and washed with acetone. The filtrate is concentrated to obtain a residue, to which water is added. This mixture is extracted with ethyl acetate, washed with saturated salt solution, dried over sodium sulfate, and the subsequent purification of the residue by chromatography gives the desired product with a yield of 85%. Alternative dibromide from the reaction with NBS can be vyletev DMSO (concentration of 10-20% of the mass) and stirred for 30 minutes at room temperature. When the reaction is complete, the reaction mixture was poured into water and the resulting precipitate was separated by filtration, the filter cake washed with water and dried, obtaining essentially quantitative yield.

Stage 5: the aldehyde from the previous step (1 EQ.) in CH3NO2(0.2 M) is added ammonium acetate (4 equiv.) and the resulting mixture is refluxed for 4 hours. Then the reaction mixture was diluted with EtOAc and washed with a saturated solution of salt. The aqueous phase is extracted with EtOAc. The combined organic extracts washed with saturated salt solution, dried over sodium sulfate and concentrated until precipitation of an orange crystalline solid. The mixture is cooled overnight and filtered to collect nitroolefins (yield 76%). Evaporation of the liquid phase and purification of the residue column chromatography (gradient elution 100% toluene→ 1% EtOAc-toluene) gives more nitroolefins (yield 23%).

Stage 6: Zinc dust (20 EQ.) suspended in 5% aqueous HCl solution (8 M Zn/5% HCl). To this mixture add HgCl2(0,28 EQ.). The mixture was shaken for 10 min, the aqueous phase is decanted and replaced with fresh 5% HCl, and again the mixture is shaken for 5 min and the aqueous phase is separated. Then thus obtained amalgam zinc-mercury added to a mixture of nitroolefins (1.0 EQ.) and Kon is enteromonas HCl (80 EQ.) in THF (0.04 M of nitroolefins/THF). The mixture is gently refluxed for 1 hour. For the formation of the product is monitored by TLC analysis. The mixture is cooled to room temperature and the solid is separated by filtration through celite. To the liquid add concentrated NH4OH and the mixture concentrated on a rotary evaporator. The residue is dissolved in CH2Cl2and concentrated NH4OH. The aqueous phase is extracted with CH2Cl2and the organic phase is washed with saturated salt solution, dried over sodium sulfate and concentrated. Purification of column chromatography gives the desired product (yield 65%).

Stage 7: To methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (1 EQ.) and saturated NaHCO3(0,14 M) in CH2Cl2(0,07 M) add α-toluensulfonate (1.0 EQ.). After 1 hour the mixture was poured into saturated sodium bicarbonate solution and extracted with CH2Cl2. The combined organic phase was washed with saturated salt solution, dried over sodium sulfate and purified column chromatography (gradient elution using a mixture of 20% EtOAc-hexane→50% EtOAc-hexane)to give the desired product with a yield of 86%.

Stage 8: the resulting ester hydrolyzing, stirring with 1 N. NaOH (5 EQ.) in THF (0,07 M) and a sufficient amount of MeOH to obtain a clear solution. The reactions which control TLC (10% MeOH-CH 2Cl2) on the extinction of the original substance. The mixture is heated in an oil bath at 60°C for 2 hours. The mixture is concentrated, diluted with H2O and acidified to pH 2-4, using 1M HCl. The aqueous phase is extracted with EtOAc and the organic phase is washed with saturated salt solution, dried over sodium sulfate and concentrated, obtaining the desired product with a yield of 92%. Mass spectrometry high resolution calc. for [C39H35ClN2O5S + H] 679,2028 found 679,2031.

Example 2:4-[2-(1-benzhydryl-5-chloro-2-{2-[(isopropylphenyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and isopropylacetanilide procedure of example 1, stage 7 with the release of 55%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 81%. MS high resolution calc. for [C35H35ClN2O5S + H] 631,2028 found 631,2029.

Example 3: 4-[2-(1-benzhydryl-2-{2-[(butylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 1-butanesulfonyl the IDA procedure of example 1, stage 7 with the release of 61%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 90%. MS high resolution calc. for [C36H37ClN2O5S + H] 645,2185 found 645,2185.

Example 4: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(1-methyl-1H-imidazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) (1.0 EQ.) and Et3N (3.0 EQ.) or pyridine (3.0 EQ.) in CH2Cl2(0.05 M) was added 1-Mei-4-sulphonylchloride (1.2 EQ.). Reaction control TLC (10% MeOH-CH2Cl2) and the mixture is heated if necessary. After 30 min the mixture was poured into saturated sodium bicarbonate solution and extracted with CH2Cl2. The combined organic phase was washed with saturated salt solution, dried over sodium sulfate and purified column chromatography, receiving 92% of the desired product.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 89%. MS high resolution calc. for [C36H33ClN4O5S + H] 669,1933 found 669,1932.

Example 5: 4-{2-[1-benzhydryl-2-(2-{[(5-bromo-6-chloro-3-PI is idini)sulfonyl]amino}ethyl)-5-chloro-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: This compound is prepared from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 3-bromo-2-chloropyridin-5-sulphonylchloride procedure of example 1, step 7 to yield 74%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 98%. MS high resolution calc. for [C37H30BrCl2N3O5S+N] 778,0539 found 778,0544.

Example 6: 4-[2-(1-benzhydryl-5-chloro-2-{2-[({[(1R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: This compound is prepared from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and (1R)-(7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonamide procedure of example 1, step 7 exit 77%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 94%. MS high resolution calc. for [C42H43ClN2O6S+N] 739,2603 found 739,26.

Example 7: 4-(2-{1-benzhydryl-5-chloro-2-[2-({[(methylsulphonyl)methyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: This compound is prepared from methyl 4-{2[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and (methanesulfonyl)methanesulfonanilide procedure of example 4, stage 1 with the release of 43%.

Stage 2: Intermediate connection representing an ester, hydrolyzing according to example 117, step 2, getting listed in the header of the acid with a yield of 95%. MS high resolution calc. for [C34H33ClN2O7S2+H] 681,1491 found 681,1489.

Example 8: 4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(1-naphthyl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: This compound is prepared from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 2-(1-naphthyl)acanaloniidae procedure of example 1, stage 7 with the release of 60%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 100%. MS high resolution calc. for [C44H39ClN2O5S+N] 743,2341 found 743,2338.

Example 9: 4-{2-[1-benzhydryl-5-chloro-2-{2-[({2-nitrobenzyl}sulfonyl)amino]ethyl}-1H-indol-3-yl]ethoxy]benzoic acid

Stage 1: This compound is prepared from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 2-nitro-α-toluensulfonate procedure of example 1, stage 7 with the release of 82%.

Stage 2: Intermediate Obedinenie, representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 85%. MS high resolution calc. for [C39H34ClN3About7S+N] 724,1879 found 724,1877.

Example 10: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: This compound is prepared from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and [(3,4-dichlorophenyl)methyl]sulphonylchloride procedure of example 1, stage 7 with the release of 82%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 86%. MS high resolution calc. for [C39H33Cl3N2CO5S+N] 747,1249 found 747,1249.

Example 11: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,5-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: This compound is prepared from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and [(3,5-dichlorophenyl)methyl]sulphonylchloride procedure of example 1, stage 7 with the release of 100%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, getting found is agolove acid with a yield of 98%. MS high resolution calc. for [C39H33Cl3N2O5S+N] 747,1249 found 747,1249.

Example 12: 4-(2-{1-benzhydryl-5-chloro-2-[2-({[3-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: This compound is prepared from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and [[3-(trifluoromethyl)phenyl]methyl]sulphonylchloride procedure of example 1, step 7 to yield 74%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 86%. MS high resolution calc. for [C40H34ClF3N2O5S+N] 747,1902 found 747,1904.

Example 13: 4-(2-{1-benzhydryl-5-chloro-2-[2-({[4-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: This compound is prepared from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and [[4-(trifluoromethyl)phenyl]methyl]sulphonylchloride procedure of example 1, step 7 exit 77%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 83%. MS high resolution calc. for [C40H34ClF3N2O 5S+N] 747,1902 found 747,1901.

Example 14: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(4-terbisil)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: This compound is prepared from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and [(4-forfinal)methyl]sulphonylchloride procedure of example 1, stage 7 with the release of 86%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 94%. MS high resolution calc. for [C39H34ClFN2O5S+N] 697,1934 found 697,1938.

Example 15: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(4-chlorbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: This compound is prepared from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and [(4-chlorophenyl)methyl]sulphonylchloride procedure of example 1, step 7 exit 73%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 99%. MS high resolution calc. for [C39H34Cl2N2O5S+N] 713,1638 found 713,1643.

Example 16: 4-{2-[2-(2-{[(2-aminobenzyl)sulfonyl]amino}ethyl)-5-chloro-1-(diphenylmethyl)-1H-indol-3-yl]E. the oxy}benzoic acid

Stage 1: To the methyl 4-{2-[1-benzhydryl-5-chloro-2-{2-[2-nitrobenzyl]benzyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoate, example 9, step 1 (1.0 EQ.) in CH2Cl2(0,014 M) add a mixture of dihydrate of tin chloride (II) (3.0 EQ.), dissolved in concentrated HCl. After 16 hours the mixture is alkalinized (pH 10) 3 N. NaOH and extracted with CH2Cl2. The combined organic phase was washed with saturated salt solution, dried over sodium sulfate and purified column chromatography (using a gradient elution of 20% EtOAc-hexane → 50% EtOAc-hexane), receiving 83% of the desired product.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 83%. MS high resolution calc. for [C39H36ClN3O5S+N] 694,2137 found 694,2136.

Example 17: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(dimethylamino)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: This compound is prepared from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and dimethylsulfoxide procedure of example 1, step 7 exit 49%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header acids is with the release of 95%. MS high resolution calc. for [C34H34ClN3O5S+N] 632,1981 found 632,1984.

Example 18: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-diferensial)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: 3,4-diferenzierbarer (1.0 EQ.) in N2O (0.74 M) add sodium sulfite (1.1 EQ.). The mixture is refluxed for 16 h, then cooled to room temperature. White precipitate is filtered and dried, obtaining 95% intermediate sulfonate sodium.

Stage 2: 3,4-differentiality sodium (7,6 EQ.) in CH2Cl2(0.76 M) is added DMF (5.6 EQ.) and SOCl2(30 EQ.). After 1 hour the mixture was concentrated and subjected to azeotropic distillation with toluene. The residue is suspended in CH2Cl2(0.38 M) and add methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) (1.0 EQ.) and saturated NaHCO3(0.76 M). After 1 hour the mixture was poured into H2O and extracted with CH2Cl2. The combined organic phase was washed with saturated salt solution, dried over sodium sulfate and purified column chromatography (using a gradient elution with 20% EtOAc-hexane → 40% EtOAc-hexane), receiving 94% of the intermediate, which represents a methyl ester.

Stage 3: methyl ester hydrolyzing in accordance with the stage 8 the use of the 1, receiving specified in the header of the acid with a yield of 93%. MS high resolution calc. for [C39H33ClF2N2O5S+N] 715,184 found 715,1843.

Example 19: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-naphthylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: Intermediate sulphonylchloride obtained from 2-(methyl bromide)naphthalene procedure of example 18, stages 1-2 with the release of 34%.

Stage 2: methyl ester obtained from sulphonylchloride and methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl] ethoxy}benzoate (step 6, example 1) by the procedure of example 1, step 7 exit 58%.

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 74%. MS high resolution calc. for [C43H37ClN2O5S+N] 729,2185 found 729,2189.

Example 20: 3-({[(2-{1-benzhydryl-3-[2-(4-carboxyphenoxy)ethyl]-5-chloro-1H-indol-2-yl}ethyl)amino]sulfonyl}methyl)benzoic acid

Stage 1: Intermediate sulphonylchloride obtained from methyl 3-(methyl bromide)benzoate procedure of example 18, stage 1-2.

Stage 2: methyl ester obtained from sulphonylchloride and methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) by the procedure of example 1, stage 7 with the release of 23%.

Stage 3: Sub is full-time connection, representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of decollato with the release of 93%. MS high resolution calc. for [C40H35ClN2O7S+N] 723,1926 found 723,1932.

Example 21: 4-(2-{1-benzhydryl-5-chloro-2-[2-({[(E)-2-phenylethenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) is added 2-phenylethanolamine procedure of example 1, step 7, when receiving the product yield 66%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 98%. MS high resolution calc. for [C40H35ClN2O5S+N] 691,2028 found 691,2034.

Example 22: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(trifluoromethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) add triftormetilfullerenov procedure of example 1, step 7, when receiving the product with the release of 49%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 100%. MS in the high-resolution calc. for [C33H28ClF3N2O5S+N] 657,1432 found 657,1435.

Example 23: 4-[2-(1-benzhydryl-5-chloro-2-{2-[(cyclopropylmethyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) add cyclopropanesulfonyl procedure of example 1, step 1, getting the product with a yield of 75%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 84%. MS high resolution calc. for [C35H33ClN2O5S+N] 629,1872 found 629,1874.

Example 24: 4-(2-{1-benzhydryl-2-[2-({[3,5-bis(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-5-chloro-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) is added 3,5-bis(trifluoromethyl)benzolsulfonate procedure of example 1, step 7, when receiving the product yield 79%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 81%. MS high resolution calc. for [C41H-33ClF6N2O5S+N] 815,1776 found 815,1776.

Example 25: 2-{[(2-{1-benzhydryl-3-[2-(4-carbosilane the si)ethyl]-5-chloro-1H-indol-2-yl}ethyl)amino]sulfonyl}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) is added methyl (2-chlorosulfonyl)benzoate procedure of example 1, step 7, getting the product out 100%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 61%. MS high resolution calc. for [C39H33ClN2O7S+N] 709,177 found 709,1772.

Example 26: 4-[2-(1-benzhydryl-5-chloro-2-{2-[(2-naphthylmethyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) is added 2-naphthalenesulfonate procedure of example 1, step 7, when receiving the product with the release of 53%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 100%. MS high resolution calc. for [C42H35ClN2O5S+N] 715,2028 found 715,2034.

Example 27: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,5-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) is added 3,5-dichlorobenzenesulfonate of proced the swarm of example 1, stage 1, receiving the product with the release of 60%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 88%. MS high resolution calc. for [C38H31Cl3N2O5S+N] 733,1092 found 733,1096.

Example 28: 4-{2-[1-benydril-5-chloro-2-(2-{[(3,4-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) is added 3,4-dichlorobenzenesulfonate procedure of example 1, step 7, when receiving the product with the release of 60%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 80%. MS high resolution calc. for [C38H31Cl3N2O5S+N] 733,1092 found 733,1094.

Example 29: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,3-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) add [(2,3-dichlorophenyl)methyl]sulphonylchloride procedure of example 1, step 7, when receiving the product yield is 50%.

Stage 2: the resulting ester hydrolyzing, paramashiva is with KOH (67 mg, 5 EQ.) in a mixture of THF (5 ml), Meon (5 ml) and N2O (2 ml). Reaction control TLC (10% MeOH-CH2Cl2) on the extinction of the original substance. The mixture is stirred over night at room temperature and then concentrated, diluted with H2O and acidified to pH 2-4, using 1M HCl. The aqueous phase is extracted with EtOAc and the organic phase is washed with saturated salt solution, dried over sodium sulfate and concentrated, obtaining the desired product with a yield of 98%. MS high resolution calc. for [C39H33Cl3N2O5S+N] 747,1249 found 747,1254.

Example 30: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) add [(2,4-dichlorophenyl)methyl]sulphonylchloride procedure of example 1, step 7, when receiving the product with the release of 98%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with stage 2 of example 29, receiving specified in the header of the acid with a yield of 90%. MS high resolution calc. for [C39H33Cl3N2O5S+N] 747,1249 found 747,1255.

Example 31: 4-(2-{1-benzhydryl-5-chloro-2-[2-(2-chlorophenylsulfonyl)ethyl]-1H-indol-3-yl}ethoxy) benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benched the Il-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) add [(2-chlorophenyl)methyl]sulphonylchloride procedure of example 1, step 7, when receiving the product yield of 86%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with stage 2 of example 29, receiving specified in the header of the acid with a yield of 90%. MS high resolution calc. for [C39H34Cl2N2O5S+N] 713,1638 found 713,1644.

Example 32: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(4-chloro-2-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) is added (4-chloro-2-nitro)phenyl]methanesulfonamide procedure of example 1, step 7, when receiving the product yield 74%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with stage 2 of example 29, receiving specified in the header of the acid with a yield of 90%. MS high resolution calc. for [C39H33Cl2N3O7S+N] 758,1489 found 758,1494.

The method I

The acid obtained according to method a or on any subsequent method can be used as a substrate for catalyzed by palladium amination reaction using a base, an amine, a phosphine ligand and a palladium reagent.

Example 3: 4-[2-(1-benzhydryl-2-{2-[(benzylmethyl)amino]ethyl}-5-morpholine-4-yl-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: In the flask is charged with Tris(dibenzylideneacetone) dipalladium (0) (0.01 EQ.), 2-(di-tert-butylphosphino)diphenyl (0,04 equiv.) tert-piperonyl sodium (2.4 EQ.) and the acid from example 1, stage 8 (1.0 EQ.). To the flask add 1.5 ml of toluene (1.0 M), followed by the addition of the research (1.2 EQ.). The reaction mixture is refluxed for five hours. The reaction mixture was partitioned between 5% hydrochloric acid and diethyl ether. The organic layer was washed with distilled water, then with saturated salt solution, dried over sodium sulfate and concentrated. The product was then purified preparative LC-MS, receiving 7,8% of the desired product. MS high resolution calc. for [C43H43N3O6S+N] 730,2945 found 730,2945.

Example 34: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-cyanobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: (2-Cyanophenyl)methanesulfonamide receive in accordance with example 18, stage 1-2 (crude yield substances 100%).

Stage 2: Given the title compound is obtained from the methyl ester of 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoic acid (step 6, example 1) and (2-cyanophenyl)methanesulfonamide procedure of example 1, step 7 in the form of a white solid with a yield of 72%.

Stage 3: Intermediate connection representing SL is iny ether, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 74%. MS (ERIE) m/z (M-1) 702,0; MS high resolution calc. for C40H35ClN3O5S (M+1): 704,1980. Found: 704,1984. E. anal. calc. for C40H34ClN3O5S: C, 68,22; N, TO 4.87; N, 5,97. Found: C, 67,92; N, 5,11; N, 5,54.

Example 35: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,5-diferensial)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: Intermediate sulphonylchloride obtained from 3,5-diferenciada procedure of example 18, stages 1-2 with access 95%.

Stage 2: methyl ester obtained from sulphonylchloride and methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) by the procedure of example 1, step 7 exit 78%.

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 83%. MS high resolution calc. for [C39H33ClF2N2O5S+N] 715,184 found 715,1842.

Example 36: 4-{2-[1-benydril-5-chloro-2-(2-{[(3-cyanobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: (3-cyanophenyl)methanesulfonamide receive in accordance with example 18, stage 1-2 (crude yield substances 100%).

Stage 2: Specified in the header is connected to the e is obtained from the methyl ester of 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoic acid (stage 6, example 1) and (3-cyanophenyl)methanesulfonamide in accordance with example 1, step 7.

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 81%. MS (ERIE) m/z (M-1) 702,1; MS high resolution calc. for C40H33ClN3O5S (M-1): 702,1834. Found: 702,1833. E. anal. calc. for C40H34ClN3O5S·0,8 H2O: C, 67,00; N, 5,00; N, 5,86. Found: C, 67,22; N, 5,19; N, 5,44.

Example 37: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(4-cyanobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: (4-cyanophenyl)methanesulfonamide receive in accordance with example 18, stage 1-2 (crude yield substances 100%).

Stage 2: Given the title compound is obtained from the methyl ester of 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoic acid (step 6, example 1) and (4-cyanophenyl)methanesulfonamide in accordance with example 1, step 7.

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 77%. MS (ERIE) m/z (M-1) 702,1; MS high resolution calc. for C40H35ClN3O5S (M+1): 704,1980. Found: 704,1981. E. anal. calc. for C40H34ClN3O5 S: C, 68,22; N, TO 4.87; N, 5,97. Found: C, 68,09; N, Equal To 4.97; N, 5,73.

Example 38: 4-(2-{1-benzhydryl-5-chloro-2-[2-({[4-(1-piperidinylcarbonyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: [4-(piperidine-1-sulfonyl)phenyl]methanesulfonamide receive in accordance with example 18, stage 1-2 (crude yield substances 100%).

Stage 2: Given the title compound is obtained from the methyl ester of 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoic acid (step 6, example 1) and 4-(piperidine-1-sulfonyl)phenyl]methanesulfonyl in accordance with example 1, step 7.

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 73%. MS (ERIE) m/z (M-1) OF 824.2; MS high resolution calc. for C44H43ClN3O7S2(M-1): 824,2236. Found: 824,2246. E. anal. calc. for C44H44ClN3O7S2·0,5H2O: C, 63,25; N, 5,43; N, 5,03. Found: C, 62,85; N, 5,64; N, With 4.64.

Example 39: 4-(2-{2-[2-({[4-(aminosulfonyl)benzyl]sulfonyl}amino)ethyl]-1-benzhydryl-5-chloro-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: (4-sulfamoylbenzoyl)methanesulfonanilide receive in accordance with example 18, stage 1-2 (crude yield substances 100%).

Stage 2: Given the title compound is obtained from m delovogo ether 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoic acid (stage 6, example 1) and (4-sulfamoylbenzoyl)methanesulfonanilide in accordance with example 1, step 7.

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 69%. MS (ERIE) m/z (M-1) 755,9; MS high resolution calc. for C39H35ClN3O7S2(M-1): 756,1613. Found: 756,1612. E. anal. calc. for C39H36ClN3O7S2: C, 61,77; N, 4,79; N, 5,54. Found: C, 61,93; N, 5,12; N, 5,19.

Example 40: 4-(2-{1-benzhydryl-5-chloro-2-[2-(4-methanesulfonylaminoethyl)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: (4-methanesulfonyl)methanesulfonanilide receive in accordance with example 18, stage 1-2 (crude yield substances 100%).

Stage 2: Given the title compound is obtained from the methyl ester of 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoic acid (step 6, example 1) and ((4-methanesulfonyl)methanesulfonanilide in accordance with example 1, step 7.

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 75%. MS (ERIE) m/z (M-1) 755,0; MS high resolution calc. for C40H38ClN2O7S2(M+1): 757,1804. Found: 757,1804. E. Ana is. calc. for C40H37ClN2O7S2·N2O: C, 61,96; N, 5,07; N 3,61. Found: C, 61,82; N, 5,10; N, 3,48.

Example 41: 4-(2-{1-benzhydryl-5-chloro-2-[2-(4-diethylaminoethylmethacrylate)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: (4-Diethylaminophenyl)methanesulfonanilide receive in accordance with example 18, stage 1-2 (crude yield substances 100%).

Stage 2: Given the title compound is obtained from the methyl ester of 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoic acid (step 6, example 1) and (4-diethylaminophenyl)methanesulfonanilide in accordance with example 1, step 7.

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 66%. MS (ERIE) m/z (M-1) 812,1; MS high resolution calc. for C43H45ClN3O7S2(M+1): 814,2382. Found: 814,2385. E. anal. calc. for C43H44ClN3O7S2·0,3H2O: C, 62,99; N, OF 5.48; N, 5,14. Found: C, 62,91; N, 5,67; N, 4,79.

Example 42: 4-{3-[1-benzhydryl-5-chloro-2-(2-phenylmethanesulfonyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: a Mixture of methyl-4-identity (5.3g, a 20.2 mmol), allyl alcohol (1.78 g, 30.3 mmol), NaHCO3(4,24 g, and 50.5 mmol), Pd(OAc)2(0.14 g, of 0.60 mmol), (H-Bu)4Br (6,55 g, a 20.2 mmol) and molecular sieves 4 Å (4.1 g) in anhydrous DMF (69 ml) was stirred at room temperature for 4 days. The reaction mixture was filtered through celite, the filtrate was poured into water and extracted with EtOAc. The organic layer was washed with saturated salt solution, dried (Na2SO4) and concentrated in vacuo. Flash chromatography (silica gel, 10-20% EtOAc-hexane) gives 2,11 g (85%based on the recovered original substance) of the desired methyl ester 4-(3-oxopropyl)benzoic acid as a transparent oily substance.

Stage 2: To a solution of 5-chloro-2-methylindole (0,86 g, 5.2 mmol) and methyl ester of 4-(3-oxopropyl)benzoic acid (1.0 g, 5.2 mmol) in methylene chloride (50 ml) is added TFU (1.78 g, 15.6 mmol), followed by triethylsilane (1,81 g, 15.6 mmol). The reaction mixture was stirred overnight, quenched with saturated solution of NaHCO3(50 ml) and the organic layer was washed with a saturated solution of NaHCO3, water, saturated salt solution and dried (Na2SO4). The solvent is removed under reduced pressure and the residue purified column flash chromatography using a mixture of 10-20% EtOAc/hexane, obtaining the desired product with a yield of 94% (1,67 g).

Stage 3: To a solution of the product from stage 2 (1.66 g, a 4.86 mmol) in DMF (20 ml) is added NaH (60% in mineral oil, 0.24 g, 5.83 mmol) in an atmosphere of N2. The mixture peremeshivayu for 1 hour at room temperature, followed by adding dropwise benzhydrylamine (1.8 g, 7,29 mmol) in DMF (5 ml). The reaction mixture was stirred at room temperature overnight. To the reaction mixture are added water (500 ml), extracted with EtOAc, washed with saturated salt solution, dried (Na2SO4) and concentrate under reduced pressure to a brown syrup, which was purified by chromatography on silica gel using a mixture of 10% EtOAc/hexane as eluent, getting 4 in the form of a white solid with a yield of 59% (1.47 g).

Stage 4: Obtained in the previous stage, the product (1,46 g, 2,87 mmol) dissolved in CCl4(14,5 ml), followed by the addition of NBS (1,02 g, 5,73 mmol) and benzoyl peroxide (2 mg). The reaction mixture is refluxed for 1 hour (until the disappearance of starting material). This mixture is cooled to room temperature, filtered and the solid is washed with CCl4. The filtrate is evaporated to a brown residue, which is dissolved in a mixture of acetone (40 ml) and water (4 ml), then to this solution was added Ag2CO3(1,75 g, and 3.16 mmol) and after stirring at room temperature overnight, it is filtered through celite, the solvent is evaporated under reduced pressure and to the residue water is added. The mixture is extracted with EtOAc, washed with saturated salt solution, dried (Na2SO4and Lipari is up to the syrup, which is cleaned with a mixture of 10% EtOAc/hexane, receiving 2-formylindole (1.13 g) with a yield of 75%. Alternative dibromide from the reaction with NBS can pour in DMSO (10-20% mass concentration) and stir for 30 minutes at room temperature. After the reaction mixture was poured into water and the resultant precipitate was separated by filtration, the filter cake washed with water and dried, obtaining essentially quantitative yield.

Stage 5: To a solution of 2-formylindole from the previous stage (0.52 g, 1 mmol) in CH3NO2(6.2 ml) is added NH4OAc (0,077 g, 1 mmol), the mixture is refluxed for 1 h, then add NH4OAc (0,077 g, 1 mmol), boiling under reflux additionally continue for 1 h, then add NH4OAc (0,077 g, 1 mmol), boiling under reflux continued for 1 hour. The reaction mixture is allowed to cool to room temperature, add EtOAc (50 ml), followed by adding 100 ml of water. The aqueous layer was extracted with EtOAc and the combined organic layers washed with saturated salt solution, dried (Na2SO4) and evaporated to a yellow foam, which is subjected to chromatographic purification using a mixture of 10% EtOAc/hexane as eluent, getting 6 as a yellow foam with a yield of 68% (range 0.38 g).

Stage 6: Zn(Hg) is obtained by adding HgCl2(3.4 g, 7.2 mm is l) to a mixture of Zn dust (34,68 g, 530,35 mmol) and 5% HCl (38 ml) in a 100 ml flask, and the mixture vigorously stirred for 10 minutes the Aqueous phase is decanted, again add 38 ml of 5% HCl and the mixture is stirred for 10 minutes the Aqueous phase is decanted. This solid is added to the vinyl nitrosoaniline 6 (15 g, 26,57 mmol) in THF (660 ml) and concentrated HCl (64,5 ml). This mixture is stirred at room temperature for 1 h, and then refluxed for 15 minutes, the Reaction mixture was cooled to room temperature and filtered through celite. To the filtrate is added an aqueous solution of NH4OH (200 ml), stirred for 15 min and the THF removed under reduced pressure. The aqueous layer was extracted with CH2Cl2combined organic layers washed with saturated salt solution, dried (Na2SO4) and concentrated to a brown foam, which is purified column chromatography, elwira first column CHCl3to remove non-polar impurities, then with a mixture of 2% Meon/CHCl3to highlight the desired amine with a yield of 46% (6,1 g).

Stage 7: amine (1 EQ.) and saturated NaHCO3(0,14 M) in CH2Cl2(0,07 M) add α-toluensulfonate (1.0 EQ.). After 1 hour the mixture was poured into saturated sodium bicarbonate solution and extracted with CH2Cl2. The combined organic phase was washed with saturated Rast is or salt, dried over sodium sulfate and purified column chromatography, receiving 84% of the desired product.

Stage 8: the resulting ester hydrolyzing, stirring with 1 N. NaOH (5 EQ.) in THF (0,07 M) and a sufficient number of Meon to obtain a clear solution. Reaction control TLC (10% MeOH-CH2Cl2) on the extinction of the original substance. The mixture is stirred over night at room temperature and then concentrated, diluted with H2O and acidified to pH 2-4, using 1M HCl. The aqueous phase is extracted with EtOAc and the organic phase is washed with saturated salt solution, dried over sodium sulfate and concentrated, obtaining the desired product with a yield of 100%. MS high resolution calc. for [C40H37ClN2O4S+N] 677,2235 found 677,224.

Example 43: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3,5-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: This compound is obtained from the intermediate synthesized in example 42, step 6, and [(3,5-dichlorophenyl)methyl]sulphonylchloride procedure of example 43, step 7, obtaining the desired product with a yield of 98%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 42, receiving specified in the header of the acid with a yield of 100%. MS high resolution calc. for [C40 35Cl3N2O4S+N] 745,1456 found 745,1458.

Example 44: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: This compound is obtained from the intermediate synthesized in example 42, step 6, and [(3,4-dichlorophenyl)methyl]sulphonylchloride procedure of example 43, step 7, obtaining the desired product with a yield of 96%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 42, receiving specified in the header of the acid with a yield of 98%. MS high resolution calc. for [C40H35Cl3N2O4S+N] 745,1456 found 745,1458.

Example 45: 4-{2-[1-benzhydryl-5-chloro-2-(2-[(methylsulphonyl)amino]ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) add methanesulfonanilide procedure of example 4, step 1, getting the product yield of 92%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 100%. MS high resolution calc. for [C33H31ClN2About5S+N] 603,1715 found 603,1717.

Example 46: 4-{2-[1-benzhydryl-5-chloro-2-{2-[(phenylsulfonyl)amino]ethyl}-1H-indol-3-the l]ethoxy}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) add benzosulphochloride procedure of example 4, step 1, getting the product yield of 90%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 90%. MS high resolution calc. for [C38H33ClN2About5S+N] 665,1872 found 665,1869.

Example 47: 4-(2-{1-benzhydryl-5-chloro-2-[2-({[3-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) add {[3-(trifluoromethyl)phenyl]methyl}sulphonylchloride procedure of example 1, step 7, when receiving the product yield 74%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 86%. MS high resolution calc. for [C40H34ClF3N2O5S+N] 747,1902 found 747,1904.

Example 48: 2-{[(2-{[(2-{1-benzhydryl-3-[2-(4-carboxyphenoxy)ethyl]-5-chloro-1H-indol-2-yl}ethyl)amino]sulfonyl}ethyl)amino]carbonyl}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, the example 1) is added 2-palmitoylethanolamide procedure of example 1, stage 7, when receiving the product yield 78%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 99%. MS high resolution calc. for [C42H38ClN3O8S+N] 780,2141 found 780,2148.

Example 49: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[pyridin-3-elmersolver]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) add (3-pyridylmethyl)sulphonylchloride procedure of example 1, step 7, when receiving the product with the release of 52%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 94%. MS high resolution calc. for [C38H34ClN3O5S-N] 678,18349 found 678,18277.

Example 50: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[pyridin-4-elmersolver]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) is added (4-pyridylmethyl)sulphonylchloride procedure of example 1, step 7, when receiving the product with the release of 57%.

Stage 2: Intermediate connection representing an ester, hydrolyzing rela is availa able scientific C with stage 8 of example 1, receiving specified in the header of the acid with a yield of 100%. m/z (M-1) MS high resolution calc. for [C38H34ClN3O5S-N] 678,18349 found 678,18249.

Example 51: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[pyridin-2-elmersolver]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) add (2-pyridylmethyl)sulphonylchloride procedure of example 1, step 7, when receiving the product with the release of 42%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 56%. MS high resolution calc. for [C38H34ClN3O5S-N] 678,18349 found 678,18312.

Example 52: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: Intermediate sulphonylchloride derived from 2,6-dimethylbenzylamine procedure of example 18, stages 1-2 with the release of 100%.

Stage 2: methyl ester obtained from sulphonylchloride and intermediate compound of example 42, step 6 the procedure of example 42, step 7 with 30%yield.

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 42, receiving specified in the header acid output is om 100%. MS high resolution calc. for [C42H41ClN2O4S-N] 703,24028 found 703,23973.

Example 53: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(cyclohexylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: Intermediate sulphonylchloride obtained from (methyl bromide)cyclohexane procedure of example 18, stages 1-2 with the release of 100%.

Stage 2: methyl ester obtained from sulphonylchloride and methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) by the procedure of example 1, stage 7 with a yield of 20%.

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 73%. MS high resolution calc. for [C39H41ClN2O5S-N] 683,23519 found 683,23474.

Example 54: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(4-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: Intermediate sulphonylchloride obtained from 4-nitrobenzylamine procedure of example 18, stages 1-2 with access 95%.

Stage 2: methyl ester obtained from sulphonylchloride and methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) by the procedure of example 1, stage 7 with the release of 80%.

Stage 3: Intermediate connection, which represents an ester hydrolyzing in accordance with the stage 8 of example 1, getting listed in the title compound with a yield of 90%. MS high resolution calc. for [C39H34ClN3O7S+N] 724,1879 found 724,1884.

Example 55: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: Intermediate sulphonylchloride obtained from 3-nitrobenzylamine procedure of example 18, stages 1-2 with access 95%.

Stage 2: methyl ester obtained from sulphonylchloride and methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) by the procedure of example 1 step 7 exit 85%.

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining mentioned in the title compound with a yield of 85%. MS high resolution calc. for [C39H34ClN3O7S+N] 724,1879 found 724,1885.

Example 56: 4-{2-[1-benzhydryl-5-chloro-2-{2-[({2-nitrobenzyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add 2-nitro-α-toluensulfonate procedure of example 1, step 7, when receiving the product with the release of 65%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, the receiving uke is annoy in the header of the acid with a yield of 100%. MS high resolution calc. for [C40H36ClN3O6S+N] 722,2086 found 722,2088.

Example 57: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(4-terbisil)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add (4-forfinal)methanesulfonanilide procedure of example 1, step 7, when receiving the product yield of 77%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 68%. MS high resolution calc. for [C40H36ClFN2O4S+N] 695,2141 found 695,2145.

Example 58: 4-(3-{1-benzhydryl-5-chloro-2-[2-({[4-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 42) add (4-triptoreline)methanesulfonanilide procedure of example 1, step 7, when receiving the product yield is 50%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 100%. MS high resolution calc. for [C41H-36ClF3N2O4S+N] 745,2109 found 745,2114.

Example 59: 4-(3-{1-Ben is hydril-5-chloro-2-[2-({[3-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add (3-triptoreline)methanesulfonanilide procedure of example 1, step 7, when receiving the product with the release of 56%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 82%. MS high resolution calc. for [C41H-36ClF3N2O4S+H] 745,2109 found 745,211.

Example 60: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(4-chlorbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add (4-chlorophenyl)methanesulfonamide procedure of example 1, step 7, when receiving the product yield 74%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 79%. MS high resolution calc. for [C40H36Cl2N2O4S+N] 711,1846 found 711,1847.

Example 61: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-pyridinylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add the feast of the DIN-2-immeasureable procedure of example 4, stage 1, receiving the product with a yield of 75%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 96%. MS high resolution calc. for [C39H36ClN3O4S+N] 678,2188 found 678,2187.

Example 62: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-pyridinylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) is added pyridine-3-immeasureable procedure of example 4, step 1, getting the product with a yield of 75%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 88%.

Example 63: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(4-pyridinylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) is added pyridine-4-immeasureable procedure of example 4, step 1, getting the product with a yield of 75%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 77%. MS h the who resolution calc. for [C39H36ClN3O4S-N] 676,20423 found 676,20405.

Example 64: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-Chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: Intermediate sulphonylchloride obtained from 3-chlorobenzylamino procedure of example 18, stage 1-2.

Stage 2: methyl ester obtained from sulphonylchloride and methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) by the procedure of example 1, stage 7 output 10%.

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining mentioned in the title compound with a yield of 100%. MS high resolution calc. for [C40H36Cl2N2O4S-N] 709,17000 found 709,16961.

Example 65: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: Intermediate sulphonylchloride obtained from 3-nitrobenzylamine procedure of example 18, stage 1-2.

Stage 2: methyl ester obtained from sulphonylchloride and methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) by the procedure of example 1, stage 7 with the release of 43%.

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, olucha specified in the title compound with yield of 88%. MS high resolution calc. for [C40H36ClN3About6S-N] 720,19405 found 720,19398.

Example 66: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-Chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: Intermediate sulphonylchloride obtained from 3-chlorobenzylamino procedure of example 18, stage 1-2.

Stage 2: methyl ester obtained from sulphonylchloride and methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) by the procedure of example 1, stage 7 with the release of 27%.

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining mentioned in the title compound with a yield of 93%. MS high resolution calc. for [C40H36Cl2N2O4S-N] 709,17000 found 709,16963.

Example 67: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,5-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: Intermediate sulphonylchloride obtained from 2,5-dichlorobenzamide procedure of example 18, stage 1-2.

Stage 2: methyl ester obtained from sulphonylchloride and methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) by the procedure of example 1, step 7 to yield 59%.

Stage 3: Intermediate connection representing an ester, hydrolyzing in the accordance with the stage 8 of example 1, getting listed in the title compound with a yield of 100%. MS high resolution calc. for [C40H35Cl3N2O4S-N] 743,13103 found 743,13079.

Example 68: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-methoxybenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: Intermediate sulphonylchloride obtained from 3-methoxybenzylamine procedure of example 18, stage 1-2.

Stage 2: methyl ester obtained from sulphonylchloride and methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) by the procedure of example 1, stage 7 with a yield of 20%.

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining mentioned in the title compound with a yield of 100%. MS high resolution calc. for [C41H-39ClN2O5S-N] 705,21954 found 705,21909.

Example 69: 4-{3-[2-(2-{[(2-aminobenzyl)sulfonyl]amino}ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoic acid

Stage 1: the Intermediate connection of stage 1 of example 56 process SnCl2the procedure described in stage 1 of example 16, receiving a complex amine ether with a yield of 99%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 100%. Svyatogo resolution calc. for [C40H38ClN3O4S-N] 690,21988 found 690,21941.

Example 70: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-methylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: Intermediate sulphonylchloride obtained from 2-methylbenzylamine procedure of example 18, stages 1-2 with a quantitative yield.

Stage 2: methyl ester obtained from sulphonylchloride and intermediate substances obtained in example 42, step 6, the procedure of example 42, step 7 with the release of 50%.

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 42, receiving specified in the header of the acid with a yield of 93%. MS high resolution calc. for [C41H-39ClN2O4S-N] 689,22463 found 689,22421.

Example 71: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(4-cryptomaterial)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: Intermediate sulphonylchloride obtained from 4-cryptomaterial procedure of example 18, stages 1-2 with a quantitative yield.

Stage 2: methyl ester obtained from sulphonylchloride and methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) by the procedure of example 1, stage 7 with the release of 48%.

Stage 3: Intermediate connection representing an ester, hydrolyzing, in compliance and with the stage 8 of example 1, receiving specified in the header of the acid with a yield of 85%. MS high resolution calc. for [C40H34ClF3N2O6S-N] 761,17054 found 761,17031.

Example 72: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-fluoro-6-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: Intermediate sulphonylchloride obtained from 2-fluoro-6-nitrobenzylamine procedure of example 18, stages 1-2 with a quantitative yield.

Stage 2: methyl ester obtained from sulphonylchloride and methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) by the procedure of example 1, stage 7 with the release of 91%.

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 100%. m/z (M-1) 740,05.

Example 73: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: Intermediate sulphonylchloride obtained from 3,5-dichlorobenzamide procedure of example 18, stages 1-2 with theoretical output.

Stage 2: methyl ester obtained from sulphonylchloride and methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl] ethoxy}benzoate (step 6, example 1) by the procedure of example 1, stage 7 with the release of 100%.

Stage 3: Intermediate connection representing SL is iny ether, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 81%. m/z (M-1) 747,2. MS high resolution calc. for [C39H33Cl3N2O5S-N] 745,11030 found 745,10954.

Example 74: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-diferensial)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: Intermediate sulphonylchloride derived from 2,6-diferenciada procedure of example 18, stages 1-2 with access 95%.

Stage 2: methyl ester obtained from sulphonylchloride and methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) by the procedure of example 1, stage 7 with the release of 86%.

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header acid with 71%yield. m/z (M-1) 714. MS high resolution calc. for [C39H33ClF2N2O5S-N] 713,16940 found 713,16906.

Example 75: 4- (2-{1-benzhydryl-5-chloro-2-[2-({[(6-chloro-3-pyridinyl)methyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: (6-chloro-3-pyridinyl)methanol (1.0 EQ.) put in dichloromethane and stirred overnight with cetarehhloristam carbon (1.5 EQ.) and 1,3-bis(diphenylphosphino)propane (0.75 EQ.). To the solution was added ether, and filtration, followed by concentri the Finance filtrate, gives (6-chloro-3-methyl bromide)pyridine to yield 62%.

Stage 2: Intermediate sulphonylchloride obtained from the product of stage 1 by the procedure of example 18, stage 1-2.

Stage 3: methyl ester obtained from sulphonylchloride and methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) by the procedure of example 1, step 7 exit 78%.

Stage 4: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 89%. MS high resolution calc. for [C38H33CI2N3O5S-N] 712,14452 found 712,14420.

Example 76: 4-(2-{1-benzhydryl-5-chloro-2-[2-({[(5,6-dichloropyridine-2-yl)methyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Step 1: 5,6-dichloro-3-pyridinemethanol (1.0 EQ.) put in dichloromethane and stirred overnight with cetarehhloristam carbon (1.5 EQ.) and 1,3-bis(diphenylphosphino)propane (0.75 EQ.). To the solution was added ether, and filtration, followed by concentration of the filtrate gives 5,6-dichloro-3-bromomethylphenyl with the release of 130%.

Stage 2: Intermediate sulphonylchloride obtained from the product of stage 1 by the procedure of example 18, stages 1-2 with exit 81%.

Stage 3: methyl ester obtained from sulphonylchloride and methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]this is si}benzoate (step 6, example 1) the procedure of example 1, step 7 exit 79%.

Stage 4: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 109%. MS high resolution calc. for [C38H32Cl3N3O5S-N] 746,10554 found 746,10549.

Example 77: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3-methoxybenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: Intermediate sulphonylchloride obtained from 3-methoxybenzylamine procedure of example 18, stages 1-2 with yield 68%.

Stage 2: methyl ester obtained from sulphonylchloride and methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl] ethoxy}benzoate (step 6, example 1) by the procedure of example 1, step 7 exit 68%.

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of decollato with the release of 93%. MS high resolution calc. for [C39H33Cl3N2About5S+Na] 731,1953 found 731,1947.

Example 78: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,5-dimethylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: Intermediate sulphonylchloride obtained from 3,5-dimethylbenzylamine procedure of example 18, stages 1-2 with 38%.

Stage 2: Complex m is tilby ether obtained from sulphonylchloride and methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) the procedure of example 1, stage 7 with 38%.

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of decollato with the release of 88%. m/z (M-1) 705,0. MS high resolution calc. for [C41H-39ClN2O5S-H] 705,21954 found 705,21916.

Example 79: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-methylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: Intermediate sulphonylchloride obtained from 2-methylbenzylamine procedure of example 18, stages 1-2 with the release of 35%.

Stage 2: methyl ester obtained from sulphonylchloride and methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) by the procedure of example 1, stage 7 with the release of 35%.

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of decollato with the release of 90%. m/z (M-1) 691,0. MS high resolution calc. for [C40H37ClN2O5S-H] 691,20389 found 691,20350.

Example 80: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: Intermediate sulphonylchloride derived from 2,6-dichlorobenzamide procedure of example 18, stages 1-2 with the release of 3%.

Stage 2: methyl Complex EF the R obtained from sulphonylchloride and methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) the procedure of example 1, step 7 exit 3%.

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of decollato with the release of 92%. m/z (M-1) 745,0.

Method

Intermediate amine synthesized using the method And handle chloromethylmethylether in terms of SCHOTT and Baumana or anhydrous conditions with an organic base, receiving the intermediate connection representing chloromethanesulfonyl. This intermediate compound can be processed in various nucleophiles in DMF in the presence of suitable organic bases, N,N-diisopropylethylamine, triethylamine, etc. and heated until the reaction is completed. Then the resulting intermediate compound hydrolyzing receiving end of the connection.

In the following examples, the synthesis is carried out according to the method With: examples 81-86 and 118-121.

Example 81: 4-(2-{1-benzhydryl-5-chloro-[2-({[(phenylsulfanyl)methyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Specified in the title compound is synthesized, as shown in method C.

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) add chloromethanesulfonyl procedure of example 1, with the adiya 7, receiving the product with a yield of 99%.

Stage 2: methyl 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(chloromethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoate (0,080 M, 1.0 EQ.) and ISO-Pr2NEt (3.4 EQ.) in N,N-dimethylformamide add thiophenol (2.1 to 2.5 EQ.) and the mixture was stirred at 120°C for 3.5 days. The reaction mixture was diluted with EtOAc and washed with water and saturated salt solution. The combined organic phase is dried over magnesium sulfate and purified flash chromatography.

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 93%. m/z (M-1) 709,11. MS high resolution calc. for [C39H35ClN2O5S2-N] 709,16031 found 709,15999.

Example 82: 4-(2-{1-benzhydryl-5-chloro-2-[2-(2,6-dimethylbenzenesulfonamide)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: To the methyl 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(chloromethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoate, example 81, step 1, add 2,6-dimethylthiophenol procedure of example 81, step 2. The product was then purified flash chromatography using a mixture of 25% EtOAc/hexane to yield 32%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 42, receiving specified in the header acid with yields of 80%.m/z (M-1) 751,0. MS high resolution calc. for [C41H-39ClN2O5S2-H] 737,19161 found 737,19128.

Example 83: 4-(2-{1-benzhydryl-5-chloro-2-[2-(2-methoxybenzenesulfonamide)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: To the methyl 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(chloromethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoate, example 81, step 1, add 2-methoxythiophene procedure of example 81, step 2. The product was then purified flash chromatography using a mixture of 30% EtOAc/hexane to yield 36%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 42, receiving specified in the header of the acid with a yield of 94%. m/z (M-1) 753,3. MS high resolution calc. for [C40H37ClN2O6S2-H] 739,17088 found 739,17052.

Example 84: 4-[2-(1-benzhydryl-5-chloro-2-{2-[({[(2-chloro-6-were)sulfanyl]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: To the methyl 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(chloromethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoate, example 81, step 1, add 2-chloro-6-methylthiophenol procedure of example 81, step 2. The product was then purified flash chromatography using a mixture of 25% EtOAc/hexane to yield 46%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 Primera, receiving specified in the header of the acid with a yield of 100%. m/z (M-1) 771,2. MS high resolution calc. for [C40H36Cl2N2O5S2-H] 757,13699 found 757,13730.

Example 85: 4-(2-{1-benzhydryl-5-chloro-2-[2-(3,5-dichlorobenzenesulfonyl)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: To the methyl 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(chloromethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoate, example 81, step 1, add 3.5 dichlorothiophene procedure of example 81, step 2. The product was then purified flash chromatography using a mixture of 25% EtOAc/hexane to yield 40%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 42, receiving specified in the header of the acid with a yield of 98%. m/z (M-1) 793,2. MS high resolution calc. for [C39H33Cl3N2O5S2-H] 777,08237 found 777,08159.

Example 86: 4-(2-{1-benzhydryl-5-chloro-2-[2-(3,4-dimethoxybenzenesulfonamide)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: To the methyl 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(chloromethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoate, example 81, step 1, add 3,4-dimethoxyphenol procedure of example 81, step 2. The product was then purified flash chromatography using a mixture of 35% EtOAc/hexane to yield 40%.

Stage 2: Intermediate connection, before the bringing an ester, hydrolyzing in accordance with the stage 8 of example 42, receiving specified in the header of the acid with a yield of 99%. m/z (M-1) 783,3. MS high resolution calc. for [C41H-39ClN2O7S2-H] 769,18144 found 769,18120.

Method D

Intermediate amine synthesized using the method And handle chloroethanesulfonate in anhydrous conditions in the presence of an organic base, receiving the intermediate connection representing vinylsulfonate. This intermediate compound can be processed in various nucleophiles in DMF in the presence of a suitable organic base, Hunigs base, triethylamine, etc. and heat until the reaction is completed. The resulting intermediate compound is then hydrolized receiving end of the connection.

In the following examples, the synthesis is carried out according to method D: examples 87-99 and 100-105, 113-117, 122-125 and 139.

Example 87: 4-(2-{1-benzhydryl-5-chloro-2-[2-(2-morpholine-4-retentionfeeling)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Specified in the title compound is synthesized, as shown in method D.

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (0.16 M, 1.0 EQ.), step 6, example 1, and triethylamine (2.3 EQ.) in THF are added dropwise 2-chloroethanesulfonate (1.2 EQ.). After 4 hours the mixture is pouring out of the t in a saturated salt solution and extracted with EtOAc. The combined organic phase is dried over magnesium sulfate and purified column chromatography, getting vinylsulfonate with a yield of 75%.

Stage 2: To the product from stage 1 in 1-propanol added morpholine. After 5 hours the reaction mixture is evaporated to dryness and then re-dissolved in EtOAc. The organic phase is washed with saturated salt solution, dried over magnesium sulfate and purified column chromatography, obtaining the desired methyl ester with a yield of 89%.

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 89%. m/z (M-1) 702,17. MS high resolution calc. for [C38H40ClN3About6S-N] 700,2535 found 700,22500.

Example 88: 4-(2-{1-benzhydryl-5-chloro-2-[2-(2-pyrazole-1-retentionfeeling)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: This compound is obtained in yield of 90% of the intermediate compound of example 87, step 1 and 1H-pyrazole procedure of example 87, step 2, except that the mixture is heated at 80°C for 18 h.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 61%. m/z (M-1) 681,24. MS high resolution calc. for [C37H35ClN 4O5S-H] 681,19439 found 681,19407.

Example 89: 4-(2-{1-benzhydryl-5-chloro-2-[2-(2-phenylenesulfonyl)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: This compound is obtained in yield is 50% of the intermediate compound of example 87, step 1 and aniline by procedure of example 87, step 2, except that the mixture is heated at 80°C for 8 days.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 98%. m/z (M-1) 706,26. MS high resolution calc. for [C40H38ClN3O5S-H] 706,21479 found 706,21452.

Example 90: 4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: This compound is obtained in yield of 82% of the intermediate compound of example 87, step 1 and 1,4-dioxa-8 azaspiro[4.5]decane procedure of example 87, step 2, except that the mixture is stirred over night.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 100%. m/z (M-1) 756,2. MS high resolution calc. for [C41H-44ClN3O7S-H] 756,25157 found 756,25142.

Example 91: 4-[2-(1-benzhydryl-5-chloro-2-{2-[({2-4-(2-pyridinyl)-1-piperazinil]ethyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: This compound is obtained in yield of 86% of the intermediate compound of example 87, step 1 and 1-pyridin-2-yl-piperazine procedure of example 87, step 2, except that the mixture is stirred over night.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 100%. m/z (M-1) 776,2. MS high resolution calc. for [C43H44ClN5O5S-H] 776,26789 found 776,26750.

Example 92: 4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(1H-1,2,4-triazole-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: This compound is obtained in yield of 64% of the intermediate compound of example 87, step 1 and 1H-[1,2,4]triazole procedure of example 87, step 2, except that the mixture is refluxed for 4 days.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 100%. m/z (M-1) 682,1. MS high resolution calc. for [C36H34ClN5O5S-H] 682,18964 found 682,18964.

Example 93: 4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(3,5-dimethyl-1H-pyrazole-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: This compound is obtained in yield of 95% and the intermediate compound of example 87, stage 1 and 3,5-dimethyl-1H-pyrazole procedure of example 87, step 2, except that the mixture is refluxed for 24 hours.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 62%. m/z (M-1) 709,2. MS high resolution calc. for [C39H39ClN4O5S-H] 709,22569 found 709,22532.

Example 94: 4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(3-methyl-1H-pyrazole-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: This compound is obtained in yield of 88% of the intermediate compound of example 87, step 1 and 3-methyl-1H-pyrazole procedure of example 87, step 2, except that the mixture is stirred over night.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, except that regulate pH to 4-5, receiving specified in the header of the acid with a yield of 86%. m/z (M-1) 695,2. MS high resolution calc. for [C38H37ClN4O5S-N] 695,21004 found 695,20951.

Example 95: 4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(4-methyl-1H-pyrazole-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: This compound is obtained in yield of 81% of the intermediate compound of example 87, stadia and 4-methyl-1H-pyrazole procedure of example 87, stage 2, except that the mixture is refluxed for 2 days.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, except that regulate pH to 4-5, receiving specified in the header of the acid with a yield of 93%. m/z (M-1) 695,2. MS high resolution calc. for [C38H37ClN4O5S-N] 695,21004 found 695,20954.

Example 96: 4-[2-(1-benzhydryl-5-chloro-2-{2-[({2-[(2R,6S)-2,6-dimethyl-1-piperidinyl]ethyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: This compound is obtained in yield of 54% of the intermediate compound of example 87, step 1 and 2,6-dimethylpiperidine procedure of example 87, step 2, except that the mixture is heated at 70°With during the night.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, except that regulate pH to 4-5, receiving specified in the header of the acid with a yield of 79%. m/z (M-1) 726,3. MS high resolution calc. for [C41H46ClN3O5S-N] 726,27739 found 726,27720.

Example 97: 4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(2-thioxo-1-imidazolidinyl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: This compound is obtained in yield of 17% of the intermediate compounds in the EPA 87, stage 1 and imidazolidin-2-thione procedure of example 87, step 2, except that the mixture is refluxed for 3 days.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, except that regulate pH to 4-5, receiving specified in the header of the acid with a yield of 88%. m/z (M-1) 715,3. MS high resolution calc. for [C37H37ClN4O5S-N] 715,18211 found 715,18161.

Example 98: 4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(1,3-thiazolidin-3-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: This compound is obtained in yield of 33% of the intermediate compound of example 87, step 1 and thiazolidine procedure of example 87, step 2, except that the mixture is refluxed over night.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, except that regulate pH to 4-5, receiving specified in the header of the acid with a yield of 93%. m/z (M-1) 702,3. MS high resolution calc. for [C37H38ClN3O5S2-N] 702,18686 found 702,18659.

Example 99: 4-(2-{1-benzhydryl-5-chloro-2-[2-(2-[1,2,3]triazole-1-retentionfeeling)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: This compound are obtained from o is home to 23% of the intermediate compound of example 87, stage 1 and 1H-[1,2,3]triazole procedure of example 87, step 2, except that the mixture is refluxed for 5 days.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, except that regulate pH to 4-5, receiving specified in the header of the acid with a yield of 100%. m/z (M-1) 682,0. MS high resolution calc. for [C36H34ClN5O5S-H] 682,18964 found 682,18933.

Example 100: 4-(3-{1-benzhydryl-5-chloro-2-[2-(2-morpholine-4-retentionfeeling)ethyl]-1H-indol-3-yl}propyl)benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate step 6, example 42 (0.16 M, 1.0 EQ.) and triethylamine (2.3 EQ.) in THF are added dropwise 2-chloroethanesulfonate (1.2 EQ.). After 4 hours the mixture was poured in a saturated salt solution and extracted with EtOAc. The combined organic phase is dried over magnesium sulfate and purified column chromatography, getting vinylsulfonate.

Stage 2: To the product from stage 1 in 1-propanol added morpholine. After 5 hours the reaction mixture is evaporated to dryness and then re-dissolved in EtOAc. The organic phase is washed with saturated salt solution, dried over magnesium sulfate and purified column chromatography, obtaining the desired methyl ester with a yield of 100%.

Stage 3: Prom which mediate the connection, representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 85%. m/z (M-1) 698,12. MS high resolution calc. for [C39H42ClN3O5S-N] 698,24609 found 698,24581.

Example 101: 4-[3-(1-benzhydryl-5-chloro-2-{2-[2-(2,6-dimethylpiperidin-1-yl)ethanolgasoline]ethyl}-1H-indol-3-yl)propyl]benzoic acid

Stage 1: This compound is obtained in yield 59% of the intermediate compound of example 100, step 1 and 2,6-dimethylpiperidine procedure of example 100, step 2, except that the mixture is refluxed at 80°within 1 day, 17 hours.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 86%. m/z (M-1) 724,20. MS high resolution calc. for [C42H48ClN3O4S-N] 724,29813 found 724,29776.

Example 102: 4-[3-(1-benzhydryl-5-chloro-2-{2-[2-(3,5-dimethylpyrazol-1-yl)ethanolgasoline]ethyl}-1H-indol-3-yl)propyl]benzoic acid

Stage 1: This compound are obtained from a quantitative yield of the intermediate compound of example 100, step 1 and 3,5-dimethyl-1H-pyrazole procedure of example 100, step 2, except that the mixture is refluxed at 80°C for 1 day.

Stage 2: Prohm is filling connection, representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 89%. m/z (M-1) 707,16. MS high resolution calc. for [C40H41ClN4O4S-H] 707,24642 found 707,24597.

Example 103 and 104: 4-(2-{1-benzhydryl-5-chloro-2-[2-(2-tetrazol-2-retentionfeeling)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

and

4-(2-{1-benzhydryl-5-chloro-2-[2-(2-tetrazol-1 retentionfeeling)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: a Mixture of methyl ester 4-{2-[1-benzhydryl-5-chloro-2-(2-atenololatenolol)-1H-indol-3-yl]ethoxy}benzoic acid (0.2 M, 1.0 EQ.), 1H-tetrazole (4.0 EQ.) and ISO-Pr2NEt (4.3 EQ.) 1-propanol is refluxed over night. The mixture is evaporated to dryness and then re-dissolved in EtOAc. The organic phase is washed with water and saturated salt solution, dried over magnesium sulfate, purified column chromatography, obtaining two isomers with yields of 41% and 52%, respectively.

Stage 2: Intermediate compounds, representing an ester, hydrolyzing in accordance with the stage 8 of example 1, except that regulate pH to 4-5, getting listed in the title acid, 4-(2-{1-benzhydryl-5-chloro-2-[2-(2-tetrazol-2-retentionfeeling)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid with a yield of 92%. m/z (M-1) 683,3; 4-(2-{1-benzhydryl-5-chloro-2-[2-(2-those whom razol-1 retentionfeeling)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid with a yield of 83%. m/z (M-1) 683,3. MS high resolution calc. for [C35H33ClN6O5S-N] 683,18489 found 683,18458; 4-(2-{1-benzhydryl-5-chloro-2-[2-(2-tetrazol-1 retentionfeeling)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid with a yield of 83%. MS high resolution calc. for [C35H33ClN6O5S-H] 683,18489 found 683,18435.

Method E

Substituted aromatic nitrosoaniline treated with atelocerata in the presence of potassium or sodium in an alcohol solvent. The resulting ester oxalate is treated with a suitable reducing agent such as iron powder, and the resulting amine is subjected to cyclization to indoles under the reaction conditions. Carboxylate then restore any reducing agent, sociallyengaged, DIBAL (diisobutylaluminium hydride), etc. and the resulting alcohol oxidized using such reagents as manganese dioxide, conditions Swarna NMO/TPAP, etc. This 2-formylindole then alkylate the processing of a strong base, such as Na/KHMDS, NaH, etc. and then alkylate suitable halide. The aldehyde is then treated with nitromethane and a base, such as ammonium acetate, receiving the intermediate vinyl nitrosoaniline, which can be restored by various agents, such galiciaminded or Zn(Hg) amalgam in HCl. The resulting amine sulfonylureas using sulphonylchloride in two-phase conditions SCHOTT and Baumana or in non-aqueous conditions in the presence of organic bases. This intermediate substance may be alkylated with a recovery in position C3 aldehyde or acetal under the action of acid Bronsted or Lewis, such as triperoxonane acid, and a reducing agent, such as triethylsilane. The resulting intermediate compound hydrolyzing base, NaOH, KOH, LiOH and a mixture of solvents, including alcohol, water, and tetrahydrofuran. The following examples 105-107 synthesis carried out according to method E.

Example 105: 4-{2-[1-benzhydryl-6-chloro-2-(2-phenylmethanesulfonyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: potassium (6,24 g) in ether at room temperature, add ethanol (40 ml, 100 ml ether), diethyloxalate (27,85 g in 60 ml of ether and 4-chloro-2-nitrotoluene (40 ml ether). The reaction mixture was stirred at room temperature for 15 h, followed by sonication for 7 hours and then pouring in cold 1 N. HCl. After neutralization of the aqueous layer was extracted with EtOAc and the combined organic layers washed with saturated salt solution and dried.

After evaporation the crude ethyl ester of 3-(4-chloro-2-nitrophenyl)-2-oxopropanoic acid direct what about the use in the next stage without further purification.

Stage 2: To the crude ethyl ether, 3-(4-chloro-2-nitrophenyl)-2-oxopropanoic acid (151 mmol) in a mixture of ethanol:glacial SPLA (1:1, vol/about., 560 ml) at room temperature add iron powder (74,4 g) and the reaction mixture is stirred at the boil under reflux for 4 hours. The mixture is filtered and evaporated, obtaining a residue, which redistribute in a mixture of dichloromethane/1 N. HCl. The organic layer was washed with 1 N. HCl, NaHCO3and saturated salt solution and dried. Evaporation followed by crystallization (DHM), gives the ethyl ester of 6-chloro-1H-indole-2-carboxylic acid in the form of a solid light yellow substance (16,8 g, 50% over two stages).

Step 3: ethyl ether, 6-chloro-1H-indole-2-carboxylic acid (to 8.57 g) in THF at 0°With added dropwise a solution of lithium aluminium hydride (1M in THF) and the reaction mixture is stirred for 3.5 hours. The mixture was quenched with H2O, 15% NaOH and H2Oh, after which it is filtered and washed with THF. Evaporation of solvent gives to 7.77 g of crude (6-chloro-1H-indol-2-yl)methanol, which is directly used in the next stage.

Stage 4: (6-chloro-1H-indol-2-yl)methanol (37,7 mmol) in THF at 0°With added manganese oxide (IV) and the mixture is stirred at room temperature for 16 hours. The mixture is filtered through celite, washed with THF and EtOAc and evaporated almost to dryness. Solid Phil is trout and washed with a cold mixture of EtOAc/hexane, getting 6-chloro-1H-indole-2-carbaldehyde (62%, for stage 2).

Stage 5: To 6-chloro-1H-indole-2-carbaldehyde (1 EQ.) in DMF at 0°With parts added NaH (1.25 equiv.) followed benzhydrylamine (1.46 equiv.) and BU4NI of 0.05 EQ.). The mixture is stirred at room temperature for 42 h, then quenched with cold 0,4 N. HCl at 0°C. After neutralization of the aqueous layer was extracted with ether, the organic layer washed with cold N2O and dried. Flash chromatography on silica gel gives 1-benzhydryl-6-chloro-1H-indole-2-carbaldehyde with the release of 40%.

Step 6: a Solution of 1-benzhydryl-6-chloro-1H-indole-2-carbaldehyde (0.5 M, 1 EQ.) and NF4OAc (1 EQ.) in nitromethane is heated at 95°C for 70 minutes the Mixture is diluted with EtOAc, washed with water and dried. Evaporation of volatile components, followed by rubbing in a mixture of ether/hexane to give 1-benzhydryl-6-chloro-2-(2-nitrovinyl)-1H-indole with the release of 48%.

Stage 7: sociallyengaged (1M in THF, 4 EQ.) in THF at 0°With added dropwise 1-benzhydryl-6-chloro-2-(2-nitrovinyl)-1H-indole (0.1 M, 1 EQ.) and the reaction mixture is stirred for 2 hours. The mixture was quenched with H2O, 15% NaOH and H2O, filtered through celite and washed with EtOAc. After evaporation the residue is purified column chromatography, obtaining 2-(1-benzhydryl-6-chloro-1H-indol-2-yl)ethylamine to yield 40%.

Step 8: To 2-(1-benzhydryl-6-chloro-1H-indol-2-yl)ethylamine is added phenylmethanesulfonyl procedure of example 1, stage 7, receiving N-[2-(1-benzhydryl-6-chloro-1H-indol-2-yl)ethyl]-s-phenylmethanesulfonyl with the release of 90%.

Stage 9: N-[2-(1-benzhydryl-6-chloro-1H-indol-2-yl)ethyl]-C-phenylmethanesulfonyl (0,033 M, 1 EQ.) in dichloromethane at 0°add methyl ester 4-(2-oksidoksi)benzoic acid (3.3 equiv.) triethylsilane (6 EQ.) and TFU (5 EQ.). The reaction mixture was stirred at room temperature for 2 days and 20 hours, followed by water treatment. Purification by chromatography on silica gel, followed by HPLC with reversed phase, gives the methyl ester of 4-{2-[1-benzhydryl-6-chloro-2-(2-phenylmethanesulfonyl)-1H-indol-3-yl]ethoxy}benzoic acid with a yield of 35%.

Stage 10: the Intermediate connection of stage 9, which represents an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 64%.

Example 106: 4-(2-{1-benzhydryl-6-chloro-2-[2-(3,4-dichlorobenzenesulfonyl)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: To 2-(1-benzhydryl-6-chloro-1H-indol-2-yl)ethylamine, example 105, step 7, add (3,4-dichlorophenyl)methanesulfonamide procedure of example 105, step 7, receiving N-[2-(1-benzhydryl-6-chloro-1H-indol-2-yl)ethyl]-S-(3,4-dichlorophenyl)methanesulfonamide with quantitative yield.

Stage 2: N-[2-(1-benzhydryl-6-chloro-1H-indol-2-yl)ethyl]-S-(3,4-dichlorophenyl)methanesulfonamide alkylate with Voss is yavlenie, as described in example 105, step 9, receiving the methyl ester of 4-(2-{1-benzhydryl-6-chloro-2-[2-(3,4-dichlorobenzenesulfonyl)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid with a yield of 38%.

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 96%. m/z (M-1) 747,27.

Example 107: 4-(2-{1-benzhydryl-6-chloro-2-[2-(3,5-dichlorobenzenesulfonyl)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: To 2-(1-benzhydryl-6-chloro-1H-indol-2-yl)ethylamine, example 105, step 7, add (3,5-dichlorophenyl)methanesulfonamide procedure of example 105, step 7, receiving N-[2-(1-benzhydryl-6-chloro-1H-indol-2-yl)ethyl]-S-(3,5-dichlorophenyl)methanesulfonamide with quantitative yield.

Stage 2: N-[2-(1-benzhydryl-6-chloro-1H-indol-2-yl)ethyl]-S-(3,4-dichlorophenyl)methanesulfonamide alkylate recovery, as described in example 105, step 9, receiving the methyl ester of 4-(2-{1-benzhydryl-6-chloro-2-[2-(3,5-dichlorobenzenesulfonyl)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid with a yield of 31%.

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 95%. MS high resolution calc. for [C39H33Cl3N2O5S+Na] 769,1068 found 769,1079.

the example 108: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-cyanobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: Intermediate sulphonylchloride obtained from 2-bromomethylbiphenyl procedure of example 18, stages 1-2 with the release of 100%.

Stage 2: methyl ester obtained from sulphonylchloride and methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) by the procedure of example 1, step 7.

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with the full output of 72%. MS high resolution calc. for C40H35ClN3O5S (M+1): 704,1980 found 704,1984.

Example 109: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(tetrahydro-2H-Piran-2-ylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: Intermediate sulphonylchloride obtained from 2-bromoethylamine procedure of example 18, stages 1-2 with the release of 100%.

Stage 2: methyl ester obtained from sulphonylchloride and methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) by the procedure of example 1, step 7.

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with the full yield of 20%. MS high resolution calc. for C38H38ClN2O6S (M-1): 685,2145 found 685,2143

Example 110: 4-{2-[1-benzhydryl-2-(2-{[(1,3-benzoxazol-2-ylmethyl)sulfonyl]amino}ethyl)-5-chloro-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: Intermediate sulphonylchloride obtained from 2-bromomethylisoxazole procedure of example 18, stages 1-2 with the release of 100%.

Stage 2: methyl ester obtained from sulphonylchloride and methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) by the procedure of example 1, step 7.

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with the full release of 26%. MS high resolution calc. for C40H35ClN3About6S (M+1): 720,1930 found 720,1924.

Example 111: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(cyanomethyl) sulfonyl] amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: Intermediate sulphonylchloride obtained from 3-methyl bromide-[1,2,4]oxadiazol procedure of example 18, stages 1-2 with the release of 100%.

Stage 2: methyl ester obtained from sulphonylchloride and methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) by the procedure of example 1, step 7.

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header acid to complete the yield of 59%. MS high resolution calc. for C34H31ClN3O5S (M+1): 628,1668 found 628,1662.

Example 112: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3-thienylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: Intermediate sulphonylchloride obtained from 3-methyl bromide 3-brometalia procedure of example 18, stages 1-2 with the release of 100%.

Stage 2: methyl ester obtained from sulphonylchloride and methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) by the procedure of example 1, step 7.

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with the full output of 25%. MS high resolution calc. for C32H31ClN2O5S2(M-1): 683,1447 found 683,1445.

Example 113: 4-[2-(1-benzhydryl-5-chloro-2-[2-(2-methylpyrrolidine-1-yl)ethanolgasoline]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: This compound is obtained from the intermediate of example 87, step 1 and 2-methylpyrrolidine the procedure described in example 87, step 2, with a yield of 91%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, except that regulate pH to 4-5, receiving specified in the header acid with you the Odom 99%. MS high resolution calc. for [C39H42ClN3O5S-N] 698,24609 found 698,24572.

Example 114: 4-[2-(1-benzhydryl-5-chloro-2-{2-[2-(2-methylpiperidin-1-yl)ethanolgasoline]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: This compound is obtained from the intermediate of example 87, step 1 and 2-methylpiperidine the procedure described in example 87, step 2, with a yield of 91%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, except that regulate pH to 4-5, receiving specified in the header of the acid with a yield of 96%. MS high resolution calc. for [C40H44ClN3O5S-N] 712,26174 found 712,26113.

Example 115: 4-[2-(1-benzhydryl-5-chloro-2-{2-[2-(2,5-dimethylpiperidin-1-yl)ethanolgasoline]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: This compound is obtained from the intermediate of example 87, step 1 and 2.5-dimethylpyrimidine the procedure described in example 87, step 2, with a yield of 81%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, except that regulate pH to 4-5, receiving specified in the header of the acid with a yield of 96%. MS high resolution calc. for [C40H44ClN3O5S-N] 712,26174 found 712,26114.

Example 116: 4-(2-{1-benzhydryl-5-chloro-2-[2-(2-thiomorpholine-4-retentionfeeling)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: This compound is obtained from the intermediate of example 87, step 1 and thiomorpholine the procedure described in example 87, step 2, with a yield of 93%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, except that regulate pH to 4-5, receiving specified in the header of the acid with a yield of 90%. MS high resolution calc. for [C38H40ClN3O5S2-H] 716,20251 found 716,20217.

Example 117: 4-(2-{1-benzhydryl-5-chloro-2-[2-(2-piperidine-1-retentionfeeling)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: This compound is obtained from the intermediate of example 87, step 1 and piperidine by the procedure described in example 87, step 2, with a yield of 99%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, except that regulate pH to 4-5, receiving specified in the header of the acid with a yield of 92%. MS high resolution calc. for [C39H42ClN3O5S2-H] 698,24609 found 698,24570.

Example 118: 4-{2-[1-benydril-5-chloro-2-(2-0-thailandandparticularlywomen)-1H-indol-3-yl]ethoxy}benzoic sour is and

Stage 1: To the methyl 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(chloromethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoate, example 81, step 1 add on-thiocresol the procedure described in example 81, steps 2 and 3. The product was then purified preparative HPLC to yield 45%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 42, receiving specified in the header of the acid with a yield of 98%. m/z (M-1) 723,07. MS high resolution calc. for [C40H37ClN2O5S2-H] 723,17596 found 723,17596.

Example 119: 4-(2-{1-benzhydryl-5-chloro-2-[2-(2-chlorpheniramineethscopolamine)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: To the methyl 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(chloromethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoate, example 81, step 1, add 2-chlorothiophenol the procedure described in example 81, step 2. The product was then purified preparative HPLC to yield 53%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 42, receiving specified in the header of the acid with a yield of 100%. m/z (M-1) 743,08. MS high resolution calc. for [C39H34Cl2N2O5S2-N] 743,12134 found 743,12111.

Example 120: 4-(2-{1-benzhydryl-5-chloro-2-[2-(2,6-dichlorobenzenesulfonyl)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid is acid

Stage 1: To the methyl 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(chloromethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoate, example 81, step 1, add 2,6-Dichlorotoluene the procedure described in example 81, step 2. The product was then purified preparative HPLC to yield 15.7% and hydrolyzing the acid with a yield of 37%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 42, receiving specified in the header of the acid with a yield of 98%. m/z (M-1) 776,93. MS high resolution calc. for [C39H33Cl3N2O5S2-N] 777,08237 found 777,08205.

Example 121: 4-(2-{1-benzhydryl-5-chloro-2-[2-(2,5-dimethoxyphenylethylamine)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: To the methyl 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(chloromethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoate, example 81, step 1, add 2.5-dimethoxyphenol the procedure described in example 81, step 2. The product was then purified flash chromatography using a mixture of 35% EtOAc/hexane to yield 65%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 42, receiving specified in the header of the acid with a yield of 99.5%. m/z (M-1) 769,18. MS high resolution calc. for [C41H-39ClN2O7S2-H] 769,18144 found 769,18121.

Example 122: 4-[2-(1-benzhydryl-5-chlorine is-2-{2-[2-(3-hydroxypyrrolidine-1-yl)ethanolgasoline]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: This compound is obtained from the intermediate of example 87, step 1 and 3-pyrrolidinone the procedure described in example 87, step 2, with a yield of 90% without purification on a column.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, except that regulate pH to 4-5, receiving specified in the header of the acid with a yield of 84%. m/z (M-1) 699,99. MS high resolution calc. for [C38H40ClN3O6S-H] 700,22535 found 700,22490.

Example 123: 4-[2-(1-benzhydryl-5-chloro-2-{2-[2-(4-hydroxypiperidine-1-yl)ethanolgasoline]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: This compound is obtained from the intermediate of example 87, step 1 and 4-hydroxypiperidine the procedure described in example 87, step 2, with a yield of 95% without purification on a column.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, except that regulate pH to 4-5, receiving specified in the header of the acid with a yield of 42%. m/z (M-1) 714,03. MS high resolution calc. for [C39H42ClN3O6S-H] 714,24100 found 714,24085.

Example 124: 4-[2-(1-benzhydryl-5-chloro-2-{2-[2-(2-dimethylaminomethylene-1-yl)ethanolgasoline]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: This soy is inania obtained from the intermediate of example 87, stage 1 and N-(2-piperidinoethyl)amine by the procedure described in example 87, step 2, with a yield of 90% without purification on a column.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, except that regulate pH to 4-5, receiving specified in the header acid with 71%yield. m/z (M-1) 754,94. MS high resolution calc. for [C42H49ClN4O5S-N] 755,30394 found 755,30344.

Example 125: 4-(2-{1-benzhydryl-5-chloro-2-[2-(2-imidazol-1-retentionfeeling) ethyl]-1H-indol-3-yl}ethoxy) benzoic acid

Stage 1: This compound is obtained in yield of 87% of the intermediate compound of example 87, step 1 and imidazole by the procedure described in example 87, step 2, except that the substance is heated at 120°With over 4.5 days.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, except that regulate pH to 4-5, receiving specified in the header of the acid with a yield of 60%. m/z (M-1) 681,17. MS high resolution calc. for [C37H35ClN4O5S-N] 681,19439 found 681,19409.

Example 126: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-diferensial)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: Intermediate sulphonylchloride derived from 2,6-differentialpressure of example 18, stage 1-2 with a quantitative yield.

Stage 2: methyl ester obtained from sulphonylchloride and methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl] propyl }benzoate (step 6, example 42) by the procedure of example 1, stage 7 with the release of 53%.

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 92%. m/z (M-1) 711,2. MS high resolution calc. for [C40H35ClF2N2O4S-N] 711,19013 found 711,18965.

Example 127: 4-{3-[1-benzhydryl-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: 2-methylindol handle intermediate compound from example 42, step 1, the procedure of example 42, step 2, obtaining the desired product with a yield of 88%.

Stage 2: the Product from the preceding stage alkylate benzhydrylamine procedure of example 42, step 3, getting the product yield 65%.

Stage 3: the Product from the previous step are oxidized using conditions described in example 42, step 4, receiving the desired 2-formylindole with the release of 85%.

Stage 4: Indole from the previous step is subjected to nitroaldol conditions described in example 42, step 6.

Stage 5: Vinyl nitrosoaniline from the previous stage to restore the conditions described in example 42, with the adiya 6, getting the desired aminoindole with the release of 39%.

Stage 6: Amin from stage 5 process (3,4-dichlorophenyl)methyl]sulphonylchloride procedure of example 43, step 7, receiving 100% of the desired product.

Stage 7: the Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 42, receiving specified in the header of the acid with a yield of 24%. MS high resolution calc. for [C40H36ClN2O4S-N] 709,1700 found 709,16951.

Example 128: 4-[3-(1-benzhydryl-2-{2-[(benzylmethyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoic acid

Stage 1: This compound is obtained from the intermediate of example 127, step 5 and α-toluensulfonate procedure of example 43, step 7, with the release of the desired product 83%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 42, receiving specified in the header of the acid with a yield of 95%. MS high resolution calc. for [C40H38N2O4S-N] 641,24795 found 641,24761.

Method F

Accordingly substituted halogenated amine reacts with triperoxonane anhydride, giving an intermediate substance, which can be handled Pdiithe catalyst in the presence of a base such as Tr is ethylamine, CuI and a suitable alkyne when heated, giving the desired intermediate indole. The primary alcohol is protected in the form of a silyl ether using siliclone, such as tert-butyldiphenylsilyl, and a base such as imidazole. Protected indole is then treated with oxalylamino, followed by methanol, which gives the desired complex oxalate ester, which can be alkilirovanii a suitable base such as cesium carbonate in acetonitrile and the halide by boiling under reflux. Then the oxalate can be restored with a suitable reducing agent such as borane. The resulting primary alcohol is converted into a halide, using, for example, CBr4and phosphine, which can then be nucleophile, such as thiophenol. The resulting thioether can oxidize a variety of oxidants, including axon and TPAP/NMO. Protection of the resulting sulfone can be removed under the action of a fluoride source such as TBAF, CsF, or HF. The resulting alcohol can be converted to a halide or mesilate, for example, using methanesulfonanilide and organic basis, which can then be replaced by sodium azide in DMF. The resulting alkylated can be restored under the action of triphenylphosphine and wet THF. Amin can be sulfonylureas action sulphonylchloride in duhf the EIT conditions SCHOTT and Bauman, the mixture of aqueous bicarbonate and dichloromethane, or in anhydrous conditions, including a mixture of dichloromethane and the organic base such as N,N-diisopropylethylamine. The resulting intermediate substance hydrolyzing using the base, NaOH, KOH, LiOH and a mixture of solvents, including alcohol, water, and tetrahydrofuran. The following examples 129-132 synthesis carried out by the method of F.

Example 129: 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propionic acid

Stage 1: 2-bromo-4-Chloroaniline (1.0 EQ.) dissolved in CH2Cl2(0.25 M), then add triethylamine and anhydride triperoxonane acid (1.1 EQ. each). The resulting mixture was stirred at room temperature for 1 hour. Then from the reaction mixture to remove the solvent and the residue purified flash chromatography with dichloromethane as eluent, obtaining the desired product with a yield of 97%. m/z (M-H)-300,0.

Stage 2: N-(2-bromo-4-chlorophenyl)-2,2,2-triptorelin (stage 1, 1.0 EQ.) mix with 3-buten-1-ol (2.0 equiv.) dichlorobis(triphenylphosphine)palladium (II) (2.5% equiv.) by triethylamine (3.0 EQ.), CuI (5% equiv.) in DMF (0.2 M) in a sealed vessel in an atmosphere of N2and heated at 120°C for 4 hours. Then the reaction mixture was diluted with ethyl acetate, washed with saturated salt solution and dry the t over Na 2SO4. Next, the solvent is evaporated and the residue purified column flash chromatography using a mixture of 2% MeOH/CH2Cl2getting described product (A) with the release of 67%. m/z (M-N)-194,09.

Stage 3: 2-(5-chloro-1H-indol-2-yl)ethanol (stage 2, 1.0 EQ.) and imidazole (2.0 EQ.) dissolved in DMF (0.3 M) at room temperature under stirring, then add tert-butylchloroformate (1.2 EQ.). The resulting mixture was kept at room temperature overnight, after which it was quenched with a saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phase is washed with water, saturated salt solution and dried over Na2SO4. The solvent is removed and the residue purified on a column with CH2Cl2as eluent, obtaining the desired product as a brown resin with a yield of 90%. m/z (M-H)-433,0.

Stage 4: 2-({[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indole (stage 3, 1.0 EQ.) dissolved in ether (0.4 M) and the solution cooled to 0°C. To the cold solution from the previous stage by vigorously stirring oxalicacid (1.2 EQ.). The reaction mixture was kept at 0°C for 1 hour, then add EtOH, followed by NEt3. The resulting mixture was then diluted with an additional amount of EtOH, then it is poured in in the. Extracted With EtOAc. The organic phase is washed with saturated salt solution, dried over Na2SO4concentrate, obtaining the desired product as a yellowish solid substance with a yield of 70%. m/z (M-H)-533,0.

Stage 5: Ethyl [2-({[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl](oxo)acetate (stage 4, 1 EQ.), Ph2CHBr (1.5 EQ.) and Cs2CO3(1.5 EQ.) mix in dry acetonitrile (0.1 M). The mixture is refluxed with stirring for 2 hours. The reaction mixture is cooled to room temperature, add water and extracted with EtOAc. The organic phase is concentrated and the residue purified on a column with CH2Cl2as eluent, obtaining the desired product as an orange resin with a yield of 45%. m/z (M+H)+701,3.

Step 6: Ethyl [1-benzhydryl-2-({[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl](oxo)acetate (stage 5, 1 EQ.) dissolved in THF (0.1 M), then add NR3·IU2S (2M in THF) (2 EQ.). The resulting mixture is refluxed with stirring overnight in an atmosphere of N2. The reaction mixture is cooled to room temperature, then slowly quenched with 1 N. NaOH. Washed with saturated salt solution, followed by extraction with EtOAc. Removal of solvent gives the desired product with a yield of 65%. m/z (M+H)+645,0.

Stage 7: 2-[1-benzy the RIL-2-({[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethanol (step 6, 1 EQ.) dissolved in CH2Cl3(0.08 M), then add 1,3-bis(diphenylphosphino)propane (DPPP, 0.75 EQ.). The solution is cooled to 0°C in an atmosphere of N2then add with stirring CBr4(1.25 EQ.). Stirring is continued for 2 hours while the temperature of the reaction mixture returns to room temperature. Remove solvent and the residue purified by passing through a short column with CH2Cl2as eluent, obtaining the desired product in quantitative yield. m/z (M+H)+708,0.

Stage 8: 1-benzhydryl-3-(2-bromacil)-2-({[tert-butyl (diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indole (stage 7, 1 EQ.) mixed with methyl-3-(4-mercaptophenyl)propionate (1.5 EQ.) and K2CO3(1.5 EQ.) in DMF (0.1 M). The resulting mixture was stirred at room temperature in an atmosphere of N2within 2 h, and then water is added, followed by extraction with ethyl acetate, washed with saturated salt solution and purification on column (CH2Cl2as eluent)to give the desired product with a yield of 80% in the form of a brown resin. m/z (M+H)+823,0.

Step 9: Methyl 3-[4-({2-[1-benzhydryl-2-({[tert-butyl (diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfanyl)phenyl]propanoate (stage 8, 1 EQ.) dissolved in acetonitrile (0.1 M), then add a molecular sieve (powder, 4 Å) and 4-methylmorpholin-IV-XID (NMO) (4 equiv.) in an atmosphere of N 2. After 5 min to the mixture H-Pr4NRuO4(TPAP) (5% equiv.). The resulting mixture is heated to 40°with stirring, and incubated for 1.5 hour. Removing the solvent, the residue is purified on a column using CH2Cl2then a mixture of 1% EtOAc/CH2Cl2as eluent, obtaining the desired product as a white foam with a yield of 44%. m/z (M+H)+855,1.

Step 10: Methyl ester of 3-[4-(2-{1-benzhydryl-2-[2-(tert-butyldiphenylsilyl)ethyl]-5-chloro-1H-indol-3-yl}econsultancy)phenyl]propionic acid (stage 9, 1 EQ.) dissolved in THF (0.1 M) and cooled to 0°With, then add n Bu4NF (1M in THF) (1.2 EQ.). The resulting mixture was stirred at 0°C for 5 min, then warmed to room temperature and stirred for 30 minutes to Remove the solvent. The residue is purified on a column with a mixture of EtOAc/CH2Cl2(from 1:9 to 1:4) as eluent, obtaining described intermediate compound in the form of a white foam with a yield of 90%. m/z (M+N)+616,20.

Stage 11: Methyl 3-[4-{2-[1-benzhydryl-5-chloro-2-(hydroxyethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate (stage 10, 1 EQ.) in dichloromethane (0.02 M) is treated at 0°With a mixture of MeSO2Cl (2 EQ.) and Et3N (2.5 EQ.) and stirred for 1 hour. The ice bath removed and the reaction mixture stirred for further 1 hour at room temperature, the village is e which it was diluted with CH 2Cl2washed NaH2PO4saturated salt solution and dried over Na2SO4. The solvent is evaporated, obtaining the desired product in quantitative yield. m/z (M+H)+695,0.

Stage 12: Methyl 3-(4-{[2-(1-benzhydryl-5-chloro-2-{2-[(methylsulphonyl)oxy]ethyl}-1H-indol-3-yl)ethyl]sulfonyl}phenyl)propanoate (stage 11, 1.0 EQ.) dissolved in DMF (0.03 M) and treated with NaN3(3.0 EQ.). The resulting mixture is heated to 60°C and stirred for 2 hours, then add water, extracted with ethyl acetate, washed with saturated salt solution and dried over Na2SO4. Evaporation of the solvent gives the desired product in quantitative yield. m/z (M+H)+641,1.

Stage 13: Methyl 3-[4-({2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate (stage 13, 1 EQ.) dissolved in THF (0.1 M) and treated with triphenylphosphine (1.1 EQ.). The reaction mixture was kept under stirring for 2 days, after which water is added, then stirred overnight. Remove the solvent, the residue is purified on a column with a mixture of 4% Meon:CH2Cl2as eluent, obtaining the described product with 71%yield. m/z (M+H)+615,2.

Stage 14: Methyl 3-[4-({2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate (stage 13, 1 EQ.) and (3,4-dichlorobenzyl)sulphonylchloride (1.1 EQ.) RAS is varaut in CH 2Cl2(0.1 M) at room temperature, then added with stirring an aqueous solution of Na2CO3. Stirring is continued for 2 hours. Then the organic phase is separated, washed with saturated salt solution, dried over Na2SO4. The solvent is evaporated, the residue is purified on a column using CH2Cl2to a mixture of 2% MeOH:CH2Cl2as eluent, obtaining the desired product with a yield of 85% in the form of a white solid. m/z (M-N)-834,9.

Stage 15: Methyl 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate (stage 14, 1.0 EQ.) dissolved in a mixture TTP:Meon (1:1) (0.1 M), then add 1 N. NaOH. The mixture is stirred over night at room temperature. The solvent is removed and the residue is dissolved in water, receiving the alkaline solution, which is neutralized with dilute HCl to precipitate the product. The solid is collected by filtration, washed with water, washed with hexane, and then dried, obtaining the desired product with a yield of 86%. MS high resolution calc. for [C41H37Cl3N2O6S2+H] 823,12314 found 823,12292.

Example 130: 3-(4-{[2-(1-benzhydryl-2-{2-[(benzylmethyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethyl]sulfonyl}phenyl)propionic acid

Stage 1: the Intermediate substance of the Rimera 129, stage 13 handle α-toluensulfonate procedure of example 129, step 14, receiving the desired compound with a yield of 94%.

Stage 2: Intermediate compound from the previous step is treated with NaOH procedure described in example 129, step 15, receiving the desired acid with a yield of 92%. MS high resolution calc. for [C41H39ClN2O6S2+H] 755,20109 found 755,20201.

Example 131: 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-diferensial)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propionic acid

Stage 1: the Intermediate compound from example 129, step 13 is processed (2,6-differenl)methanesulfonanilide procedure of example 129, step 14, receiving the desired compound with a yield of 42%.

Stage 2: Intermediate compound from the previous step is treated with NaOH procedure described in example 129, step 15, receiving the desired acid with a yield of 83%. MS high resolution calc. for [C41H-37ClF2N2O6S2+H] 791,18224 found 791,18257.

Example 132: 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-terbisil)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propionic acid

Stage 1: the Intermediate compound from example 129, step 13 is treated with (2-forfinal)methanesulfonanilide procedure of example 129, step 14, receiving the desired compound with a yield of 42%.

Stage 2: the Ex is offered by the connection from the previous stage is treated with NaOH procedure described in example 129, step 15, receiving the desired acid with a yield of 86%. MS high resolution calc. for [C41H38ClFN2O6S2+H] 773,19166 found 773,19213.

Method G

The intermediate compound from method F can be alkilirovanii in position C3 aldehydes or the corresponding acetals in the presence of Lewis acids or Bronsted, such as Ateret of boron TRIFLUORIDE or triperoxonane acid. The nitrogen atom of the indole you can then alkilirovanii processing strong base, such as bis(gramatically)sodium amide, n-BuLi, sodium hydride or potassium hydride in a solvent such as DMF, DMSO or THF, followed by exposure to a suitable halide. The resulting thioether can oxidize various oxidants, including axon and TPAP/NMO. With the resulting sulfone you can remove the protection under the action of a fluoride source such as TBAF, CsF, or HF. The resulting alcohol can be converted into a halide or mesilate, for example, using methanesulfonanilide and organic basis, which can then be replaced by sodium azide in DMF. The resulting alkylated can be restored under the action of triphenylphosphine and wet THF. Amin can be sulfanilamide under the action of sulphonylchloride in two-phase conditions SCHOTT and Bauman, the water mixture is about bicarbonate and dichloromethane, or in anhydrous conditions, including a mixture of dichloromethane and the organic base such as N,N-diisopropylethylamine. The resulting intermediate compound hydrolyzing using the base, NaOH, KOH, LiOH and a mixture of solvents, including alcohol, water, and tetrahydrofuran. The following examples 133, 135-138 and 140-141 synthesis carried out according to the method of G.

Example 133: 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-Chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propionic acid

Stage 1: Ethyl ester of 3-[4-(2-oxoethylidene)phenyl]propionic acid (example 129, step 3, 4.2 EQ.) add to the solution containing 2-({[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indole (1 EQ.), TFU (3 equiv.) and 1,2-dichloroethane (0.1 M) at 0°C in an atmosphere of N2. Then add Et3SiH (12 equiv.) the reaction mixture is allowed to warm to room temperature and stirred over night. The reaction mixture was quenched with aqueous NaHCO3, extracted with EtOAc, washed with saturated salt solution and dried over sodium sulfate. Purified on a column of silica gel using a mixture of 1:5 EtOAc/hexane as eluent. Obtain ethyl 4-({2-[2-(2-{[tert-butyl (diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfanyl)propanoate (yellow oily substance) with the release of 79%.

Step 2: Ethyl 4-({2-[2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfa what Il)propanoate (1 EQ.) add to a suspension of NaH (1.1 EQ.) in DMF (0.38 M) at 0° C in an atmosphere of N2. After 30 minutes, add Ph2CHBr and the reaction mixture is heated to room temperature. After 2.5 hours, the reaction mixture was quenched with NH4Cl(aq), extracted with a mixture of EtOAc/Et2O, washed with water and saturated salt solution and dried over sodium sulfate. Purified on a column of silica gel using a mixture of 1:6 EtOAc/hexane. Obtain ethyl 3-[4-({2-[1-benzhydryl-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfanyl)phenyl]propanoate (yellow resin) with a yield of 42%.

Stage 3: To a solution/suspension containing ethyl 3-[4-({2-[1-benzhydryl-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfanyl)phenyl]propanoate (1 EQ.), Acrylonitrile (0.1 M) and molecular sieves (1 g/mmol of propanoate), in an atmosphere of N2added NMO (4 EQ.). After 10 minutes add TRAR of 0.05 EQ.) and the mixture is heated to 40°C. After 2 hours the reaction mixture is cooled and filtered and the filtrate collected. Purified on a column of silica gel using a mixture of 1:4 EtOAc/hexane. Obtain ethyl 3-[4-({2-[1-benzhydryl-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate (white solid) with a yield of 86%.

Stage 4: To a solution of ethyl 3-[4-({2-[1-benzhydryl-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate (1 EQ.) and THF (0.1 M) at 0°C in an atmosphere of N2to ablaut tetrabutylammonium fluoride (1 M in THF) (1.2 EQ.). The reaction mixture is heated to room temperature and after 30 minutes, quenched with NH4Cl(aq). Extracted with EtOAc, washed with saturated salt solution and dried over sodium sulfate. Purified on a column of silica gel using a mixture of 1:9 EtOAc/CH2Cl2. Obtain ethyl 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate (white solid) with a yield of 88%.

Stage 5: To a solution of ethyl 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate (1 EQ.) in CH2Cl2(0.02 M) at 0°C in an atmosphere of N2add CH3SO2Cl (2 EQ.) and Et3N (2.5 EQ.). After 1 hour the reaction mixture is heated to room temperature. After another hour, water is added, extracted with CH2Cl2, washed with saturated salt solution and dried over sodium sulfate. Remove the solvent, obtaining ethyl 3-(4-{[2-(1-benzhydryl-5-chloro-2-{2-[(methylsulphonyl)oxy]ethyl}-1H-indol-3-yl)ethyl]sulfonyl}phenyl)propanoate (white solid) with a yield of 98%.

Step 6: Ethyl 3-(4-{[2-(1-benzhydryl-5-chloro-2-{2-[(methylsulphonyl)oxy]ethyl}-1H-indol-3-yl)ethyl]sulfonyl}phenyl)propanoate (1 EQ.), sodium azide (5 EQ.), and DMF (0.05 M) is mixed in an atmosphere of N2and heated to 60°C. After 1 hour the reaction mixture is cooled and water is added. Extracted with a mixture of EtOAc/Et2O, washed with water insystem salt solution and dried over sodium sulfate. Remove the solvent, obtaining ethyl 3-[4-({2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate (solid light brown substance) with the release of 96%.

Step 7: Ethyl 3-[4-({2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate (1 EQ.), PPh3(printed on polymer) (1.3 EQ.) and THF (0.1 M) is mixed in an atmosphere of N2. After 3 days add water (1 ml/1 mmol of propanoate) and the reaction mixture was stirred over night. Filter and collect the filtrate. Purified on a column of silica gel using a mixture of 2% Meon in CH2Cl2. Obtain ethyl 3-[4-({2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate (solid light brown substance) with the release of 65%.

Step 8: To a mixture of ethyl 3-[4-({2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate (1 EQ.), CH2Cl2(0.08 M), water (1 ml/1 ml of CH2Cl2and Na2CO3(2.5 EQ.) add (2 Chlorobenzyl)sulphonylchloride (2.2 EQ.). After 2 hours, add another (2 Chlorobenzyl)sulphonylchloride (1.1 EQ.). After another 1.5 hours, the organic layer is separated, washed with saturated salt solution and dried over sodium sulfate. Purify by preparative silikagelevye plate using a mixture of 2% Meon in CH2Cl2. Obtain ethyl 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-Chlorobenzyl)sulfonyl]amino}ethyl)-1H-Indo) - Rev.-3-yl]ethyl}sulfonyl)phenyl]propanoate (light yellow resin) with a yield of 75%.

Step 9: Ethyl 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-Chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate (1 EQ.), THF (0.1 M), Meon (1 ml/1 ml THF) and NaOH (1 BC) (11 EQ.) mix together during the night. The solvents were removed and the resulting residue is placed in water. The solution is acidified with 1 N. hydrochloric acid and collected by filtration the precipitate. Receive 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-Chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propionic acid (solid light brown substance) with the release of 83%. MS high resolution calc. for [C39H36ClN3O4S+N] 789,16211 found 789,16311.

Method N

Appropriately substituted indole-2-carboxylate can be restored with a suitable reducing agent, such as sociallyengaged, dibal, etc. and then the resultant alcohol can be to oxidize 2-formylindole using MnO2in oxidizing conditions Swarna or other oxidants. The nitrogen atom of the indole you can then alkilirovanii processing strong base, such as sodium bis(trimethylsilyl)amide, n-BuLi, sodium hydride or potassium hydride, in a solvent such as DMF, DMSO or THF, followed by exposure to a suitable halide. Then the aldehyde is treated with nitromethane and base the cation, such as ammonium acetate, receiving the intermediate vinyl nitrosoaniline that you can recover a variety of agents such as lithium aluminum hydride or Zn(Hg) amalgam in HCl. The resulting amine sulfonylureas using sulphonylchloride in two-phase conditions SCHOTT and Baumana or anhydrous conditions with an organic base. Processing the resulting sulfonamida strong base, such as sodium bis(trimethylsilyl)amide, n-BuLi, sodium hydride or potassium hydride in a solvent such as DMF, DMSO or THF, followed by the impact of similiarity, such as tert-butyldimethylsilyloxy, gives a protected sulfonamide. This substance can be formulirovat on C3, using standard conditions of Vilsmeier, a mixture of POCl3/DMF. Thus obtained 3-formylindole miniroot with recovery, using a suitable amine, a reducing agent, such as triacetoxyborohydride sodium, and acid, such as glacial acetic acid. The resulting intermediate compound hydrolyzing using the base, NaOH, KOH, LiOH and a mixture of solvents, including alcohol, water, and tetrahydrofuran. Example 134 was synthesized according to method N.

Example 134: 4-({[(1-benzhydryl-2-{2-[(benzylmethyl)amino]ethyl}-5-chloro-1H-indol-3-yl)methyl]amino}methyl)benzoic acid

Stage 1: Ethyl ester of 5-chloro-1H-shall ndol-2-carboxylic acid (1 EQ.) dissolved in THF (0.4 M), purge with nitrogen, the mixture is then cooled to 0°and slowly add sociallyengaged (3 EQ. 1M solution in THF). The reaction mixture is allowed to slowly warm to room temperature and stirred until TLC analysis indicates complete reaction. After cooling the flask to 0°slowly add NaOH (60 ml of a 3 n solution) and the reaction mixture is stirred until the formation of two layers. The layers separated, the aqueous layer was extracted 2 times with ethyl acetate, the combined organic layers washed with saturated salt solution, then dried over magnesium sulfate and concentrated, obtaining the desired alcohol, which is used crude in the next stage.

Stage 2: the Product from the previous step (1 EQ.) dissolved in THF (0.5 M), is treated with manganese dioxide (3 EQ.) and stirred for 1.5 hours, until TLC analysis indicates complete reaction. The reaction mixture was filtered through celite, dried over magnesium sulfate and concentrated, obtaining the desired crude aldehyde yield of 82%.

Stage 3: To the indole from the previous step (1.0 EQ.) in DMF (0.36 M) at 25°With added NaH (1.2 EQ., 60% dispersion in oil) and the brown solution is stirred at a temperature of from 0 to -5°C for 1 h, then add bromodiphenylmethane (1.1 EQ.) and then the reaction mixture was stirred over night. Then the reaction mixture was quenched with water, RA is billaut with ethyl acetate, washed with water and saturated salt solution, dried over sodium sulfate and purified column chromatography, receiving 60% of the desired product.

Stage 4: the above aldehyde (1.0 EQ.) in CH3NO2(0,075 M) is added ammonium acetate (9 EQ.) and the resulting mixture refluxed overnight. The reaction mixture is concentrated to small volume, then diluted with EtOAc and washed with a saturated solution of salt. The aqueous phase is extracted with EtOAc. The combined organic extracts washed with saturated salt solution, dried over sodium sulfate, concentrated and purified column chromatography to desired nitroolefins (51%yield).

Stage 5: Zinc dust (20 EQ.) suspended in 5% aqueous HCl solution (8 M Zn/5% HCl). To this mixture add HgCl2(0,28 EQ.). The mixture was shaken for 10 min, the aqueous phase is decanted and replaced with fresh 5% HCl, the mixture was again shaken for 5 min and the aqueous phase is removed. Thus obtained zinc-mercury amalgam is then added to the mixture of nitroolefins (1.0 EQ.) and concentrated HCl (80 EQ.) in THF (0.04 M of nitroolefins/THF). The mixture is gently refluxed for 1 hour. For the formation of the product watch TLC. The mixture is cooled to room temperature and the solid removed by filtration through celite. To the solution phase add koncentrirovannyh NH 4OH and the mixture concentrated on a rotary evaporator. The residue is dissolved in CH2Cl2and concentrated NH4OH. The aqueous phase is extracted with CH2Cl2, the organic phase is washed with saturated salt solution, dried over sodium sulfate and concentrated, obtaining the desired crude amine (100%), which is used in the next stage without purification.

Stage 7: The amine from the previous step (1.0 EQ.) and saturated NaHCO3(0,14 M) in CH2Cl2(0,07 M) add α-toluensulfonate (1.0 EQ.). After 1 hour the mixture was poured into saturated sodium bicarbonate solution and extracted with CH2Cl2. The combined organic phase was washed with saturated salt solution, dried over sodium sulfate and purified column chromatography (gradient elution using a mixture of 10% EtOAc-hexane → 20% EtOAc-hexane), receiving 40% of the desired sulfonamida.

Stage 8: the Sulfonamide of the preceding stage is dissolved in DMF (0.5 M) under nitrogen atmosphere, cooled to 0°C, treated with sodium hydride (1.05 of EQ. 60% oil dispersion), stirred for 15 minutes, to ensure the generation of anion, treated with tert-butyldimethylsilyloxy (1.2 EQ.) and then stirred for two hours at 0°C, after which TLC analysis shows that the reaction is complete. The reaction mixture is processed is up, distribute mixture between ½ saturated solution of ammonium chloride and ethyl acetate, extragere aqueous layers with ethyl acetate (2×), washing the combined organic layers with saturated salt solution (1×), exposing dried over magnesium sulfate and concentrating, getting the desired crude protected sulfonamide with a quantitative yield.

Step 9: To a DMF (˜1 ml) is added phosphorus oxychloride (1.2 equiv.) these reagents are stirred for 10 minutes and then add a solution of indole (1 EQ.) in DMF (0.8 M) from the previous stage. The resulting red reaction mixture is stirred for 4 hours, diluted with water, then regulate pH to 8 (the total amount of water added is about ¾ added at the beginning of DMF, then the reaction mixture is refluxed for 2 hours and finally cooled, extracted with dichloromethane, the aqueous layer was extracted with dichloromethane (2×), the combined organic layers washed with saturated salt solution (1×), dried over magnesium sulfate and concentrated, obtaining the crude aldehyde, which is used without further purification, with a yield of 75%.

Stage 10: the aldehyde from the previous step (1 EQ.) in THF (1.2 M) add methyl ester 4-aminometilbensana acid (1.2 equiv.) triacetoxyborohydride sodium (1.5 EQ.) and acetic acid(glacial, 1.5 EQ.). The reaction mixture was stirred overnight, then treated by adding a saturated solution of sodium bicarbonate and ethyl acetate, the layers separated, the aqueous layer was extracted with dichloromethane (2×), the combined organic layers washed with saturated salt solution (1×), dried over magnesium sulfate, concentrated and purified by chromatography, obtaining the desired product with a yield of 37%.

Stage 11: the resulting ester hydrolyzing, stirring 1 N. NaOH (5 EQ.) in a mixture of THF (0,07 M) and a sufficient number of Meon to obtain a clear solution. Reaction control TLC (10% MeOH-CH2Cl2) on the extinction of the original substance. The mixture is stirred at room temperature for 72 hours. The mixture is concentrated, diluted with H2O and acidified to pH 5 using 1M HCl. The aqueous phase is extracted with EtOAc, the organic phase is washed with saturated salt solution, dried over sodium sulfate and concentrated, obtaining the desired product with a yield of 83%. MS high resolution calc. for [C39H36ClN3O4S-N] 676,20423 found 676,20397.

Example 135: 4-{[2-(1-benzhydryl-2-{2-[(benzylmethyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethyl]sulfonyl}benzoic acid

Step 1: To a solution containing tert-butyldiphenylchlorosilane (1.2 equiv.) the imidazole (2.5 EQ.) and DMF (1.8 M) (in nitrogen atmosphere), add 2-(5-chloro-1H-ind the l-2-yl)ethanol (1 EQ.). The reaction mixture was stirred over night. Quenched with NaHCO3(aq)and extracted with a mixture of Et2O/EtOAc. The organic layer is washed with water, saturated salt solution and dried over sodium sulfate. Purified on a column of silica gel and a mixture of 1:4 hexane/CH2Cl2as eluent. Get 2-({[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indole (yellow oily substance) with the release of 98%.

Stage 2: To a solution containing 2-({[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indole (1 EQ.), TFU (3 EQ.) and 1,2-dichloroethane (0.1 M)at 0°and in an atmosphere of N2add methyl 4-[(2-oxoethyl)sulfanyl]benzoate (3.7 EQ.). Then add Et3SiH (12 equiv.) the reaction mixture is allowed to warm to room temperature and stirred over night. Quenched with NaHCO3(aq), extracted with EtOAc, washed with saturated salt solution and dried over sodium sulfate. Purified on a column of silica gel using a mixture of 1:5 EtOAc/hexane as eluent. Obtain methyl 4-({2-[2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfanyl)benzoate (solid yellow substance) with the release of 79%.

Stage 3: Methyl 4-({2-[2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfanyl)benzoate (1 EQ.) add to a suspension of NaH (1.1 EQ.) in DMF (0,37 M) at 0°and in an atmosphere of N2. After 30 minutes, add Ph2CHBr (1,8 the square) and the reaction mixture is heated to room temperature. After 3 hours the reaction mixture was quenched with NH4Cl(aq), extracted with a mixture of EtOAc/Et2O, washed with water and saturated salt solution and dried over sodium sulfate. Purified on a column of silica gel using a mixture of 1:5 EtOAc/hexane as eluent. Obtain methyl 3-[4-({2-[1-benzhydryl-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (yellow resin) with a yield of 65%.

Stage 4: To a solution/suspension containing methyl 3-[4-({2-[1-benzhydryl-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (1 EQ.), Acrylonitrile (0.1 M) and molecular sieves (1 g/mmol benzoate), in an atmosphere of N2added NMO (4 EQ.). After 10 minutes add TRAR (0,12 EQ.) and the mixture is heated to 40°C. After 1.5 hours the reaction mixture is cooled, filtered and the filtrate collected. Purified on a column of silica gel using a mixture of 1:5 EtOAc/hexane. Obtain methyl 3-[4-({2-[1-benzhydryl-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (white solid) with a yield of 71%.

Stage 5: To a solution of methyl 3-[4-({2-[1-benzhydryl-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (1 EQ.) in THF (0.1 M) at 0°C in an atmosphere of N2add tetrabutylammonium fluoride (1 M in THF) (1.2 EQ.). The reaction mixture is heated to room temperature the s and after 1 hour, quenched with NH 4Cl(aq). Extracted with EtOAc, washed with saturated salt solution and dried over sodium sulfate. Purified on a column of silica gel using a mixture of 1:9 EtOAc/CH2Cl2. Obtain methyl 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (white solid) with a yield of 86%.

Step 6: To a solution of methyl 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (1 EQ.) in CH2Cl2(0.02 M) at 0°C in an atmosphere of N2add CH3SO2Cl (2 EQ.) and Et3N (2.5 EQ.). After 1 hour the reaction mixture is heated to room temperature. After an additional hour, water is added, extracted with CH2Cl2, washed with saturated salt solution and dried over sodium sulfate. Remove the solvent, obtaining methyl 3-(4-{[2-(1-benzhydryl-5-chloro-2-{2-[(methylsulphonyl)oxy]ethyl}-1H-indol-3-yl)ethyl]sulfonyl}phenyl)benzoate (solid light yellow substance) with a yield of 99%.

Step 7: Methyl 3-(4-{[2-(1-benzhydryl-5-chloro-2-{2-[(methylsulphonyl)oxy]ethyl}-1H-indol-3-yl)ethyl]sulfonyl}phenyl)benzoate (1 EQ.), sodium azide (5 EQ.) and DMF (0.05 M) unite in an atmosphere of N2and heated to 60°C. After 1 hour the reaction mixture is cooled and water is added. Extracted with a mixture of EtOAc/Et2O, washed with water, saturated salt solution and dried over sodium sulfate. The daring is t a solvent, receiving methyl 3-[4-({2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (solid light yellow substance) with a yield of 99%.

Step 8: Methyl 3-[4-({2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (1 EQ.), PPh3(2 EQ.) and THF (0.1 M) unite in an atmosphere of N2and stirred over night. Add water (1 ml/1 mmol benzoate) and the reaction mixture is again stirred overnight. The solution is concentrated and purified on a column of silica gel using a mixture of 3:1 EtOAc/hexane and the mixture is then 5% Meon in CH2Cl2. Obtain methyl 3-[4-({2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (solid light yellow substance) with a yield of 99%.

Step 9: To a mixture of methyl 3-[4-({2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (1 EQ.), CH2Cl2(0,08M), water (1 ml/1 ml of CH2Cl2and Na2CO3(2.5 EQ.) add alpha toluensulfonate (2 EQ.). After 2 hours, the organic layer is separated, washed with saturated salt solution and dried over sodium sulfate. Purify by preparative silikagelevye plate using 3% Meon in CH2Cl2. Obtain methyl 4-{[2-(1-benzhydryl-2-{2-[(benzylmethyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethyl]sulfonyl}benzoate (off-white substance) with the release of 94%.

Step 10: Methyl 4-{[2-(1-benzhydryl-2{2-[(benzylmethyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethyl]sulfonyl}benzoate (1 EQ.), THF (0.1 M), Meon (1 ml/1 ml THF) and NaOH (1 BC) (11 EQ.) stirred over night. The solvents were removed and the resulting residue is transferred into the water. The solution is acidified with 1 N. hydrochloric acid and collected by filtration of the resulting precipitate. Get 4-{[2-(1-benzhydryl-2-{2-[(benzylmethyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethyl]sulfonyl}benzoic acid (off-white substance) with the release of 92%. MS high resolution calc. for [C39H35ClN2O6S2-N] 725,15523 found 725,15437.

Example 136: 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorbenzoyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoic acid

Step 1: To a mixture of methyl 3-[4-({2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (example 135, step 8, 1 EQ.), CH2Cl2(0.08 M), water (1 ml/1 ml of CH2Cl2and Na2CO3(2.5 EQ.) add (2 Chlorobenzyl)sulphonylchloride (3.4 EQ.). After 2 hours, add (2 Chlorobenzyl)sulphonylchloride (3.4 EQ.). After an additional 1.5 hours, the organic layer is separated, washed with saturated salt solution and dried over sodium sulfate. Purify on silikagelevye preparative plate using 3% Meon in CH2Cl2. Obtain methyl 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-Chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (orange resin with 40%.

Stage 2: Methyl 3[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-Chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (1 EQ.), THF (0.1 M), Meon (1 ml/1 ml THF) and NaOH (1 BC) (11 EQ.) mix together during the night. The solvents were removed and the resulting residue is transferred into the water. The solution is acidified with 1 N. hydrochloric acid and collected by filtration of the resulting precipitate. Receive a 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-Chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoic acid (solid red-orange substance) with yields of 80%. MS high resolution calc. for [C39H34Cl2N2O6S2+H] 761,13081 found 761,13146.

Example 137: 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-diferensial)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoic acid

Step 1: To a mixture of methyl 3-[4-({2-[2-(2-amino-ethyl-1)-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (example 135, step 8, 1 EQ.), CH2Cl2(0.08 M), water (1 ml/1 ml of CH2Cl2and Na2CO3(2.5 EQ.) add (2,6-diferensial)sulphonylchloride (3.4 EQ.). After 2 hours, the organic layer is separated, washed with saturated salt solution and dried over sodium sulfate. Purify on silikagelevye preparative plate using 3% Meon in CH2Cl2. Obtain methyl 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-diferensial)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate (solid off-white substance) with the release of 87%.

Stage 2: Methyl 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-debtors nil)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate (1 EQ.), THF (0.1 M), Meon (1 ml/1 ml THF) and NaOH (1 BC) (11 EQ.) mix together during the night. The solvents were removed and the resulting residue is transferred into the water. The solution is acidified with 1 N. hydrochloric acid and collected by filtration of precipitated in the sediment. Receive a 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-diferensial)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoic acid (solid white-yellow substance) with the release of 96%. MS high resolution calc. for [C39H33ClF2N2O6S2-N] 761,13638 found 761,13565.

Example 138: 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-terbisil)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoic acid

Step 1: To a mixture of methyl 3-[4-({2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (example 135, step 8, 1 EQ.), CH2Cl2(0.08 M), water (1 ml/1 ml of CH2Cl2and Na2CO3(2.5 EQ.) add (2-terbisil)sulphonylchloride (3.4 EQ.). After 2 hours, the organic layer is separated, washed with saturated salt solution and dried over sodium sulfate. Purify on silikagelevye preparative plate using 3% Meon in CH2Cl2. Obtain methyl 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-terbisil)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate (solid off-white substance) with the release of 82%.

Stage 2: Methyl 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-terbisil)sulfone is]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate (1 EQ.), THF (0.1 M), Meon (1 ml/1 ml THF) and NaOH (1 BC) (11 EQ.) mix together during the night. The solvents were removed and the resulting residue is transferred into the water. The solution is acidified with 1 N. hydrochloric acid and collected by filtration of precipitated in the sediment. Receive a 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-terbisil)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoic acid (solid off-white substance) with a yield of 99%. MS high resolution calc. for [C39H34ClFN2O6S2-N] 743,1458 found 743,14511.

Example 139: 4-(2-{1-benzhydryl-5-chloro-2-[2-(2-pyrrolidin-1 retentionfeeling)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: the Compound is prepared from intermediate compound of example 87, step 1 and pyrrolidine procedure of example 87, step 2 to yield 92% without purification on a column.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, except that regulate pH to 4-5, receiving specified in the header of the acid with a yield of 92%. MS high resolution calc. for [C38H40ClN3O5S-N] 684,23044 found 684,23009.

Example 140: 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoic acid

Step 1: To a mixture of methyl 3-[4-({2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]b is soata (example 135, stage 8, 1 EQ.), CH2Cl2(0.08 M), water (1 ml/1 ml of CH2Cl2and Na2CO3(2.5 EQ.) add (3,4-dichlorobenzyl)sulphonylchloride (2.1 EQ.). After 1 hour, the organic layer is separated, washed with saturated salt solution and dried over sodium sulfate. Purify on silikagelevye preparative plate using 3% Meon in CH2Cl2. Obtain methyl 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate (white solid) with a yield of 87%.

Stage 2: Methyl 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate (1 EQ.), THF (0.1 M), Meon (1 ml/1 ml THF) and NaOH (1 BC) (11 EQ.) mix together during the night. The solvents were removed and the resulting residue is transferred into the water. The solution is acidified with 1 N. hydrochloric acid and collected by filtration of precipitated in the sediment. Receive a 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoic acid (solid light yellow substance) with the release of 93%. MS high resolution calc. for [C38H33Cl3N2O6S2-H] 793,07728 found 793,07629.

Example 141: 4-({2-[1-benydril-5-chloro-2-(2-{[(2,6-dimethylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoic acid

Step 1: To a mixture of methyl 3-[4-({2-[2-(2-amino-ethyl)-1-benched the Il-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (example 135, stage 8, 1 EQ.), CH2Cl2(0.08 M), water (1 ml/1 ml of CH2Cl2and Na2CO3(2.5 EQ.) add (2,6-dimethylbenzyl)sulphonylchloride (3.0 EQ., example 52, step 1). After 2 hours, the organic layer is separated, washed with saturated salt solution and dried over sodium sulfate. Purify on silikagelevye preparative plate using 3% Meon in CH2Cl2. Obtain methyl 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate (solid light brown substance with 81%.

Stage 2: Methyl 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate (1 EQ.), THF (0.1 M), Meon (1 ml/1 ml THF) and NaOH (1 BC) (11 EQ.) mix together during the night. The solvents were removed and the resulting residue is transferred into the water. The solution is acidified with 1 N. hydrochloric acid and collected by filtration of precipitated in the sediment. Receive a 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoic acid (white solid) with a yield of 99%. MS high resolution calc. for [C41H39ClN2O6S2+H] 753,18653 found 753,18597.

Method J

Method J offers an alternative reaction scheme for a subset of the compounds contained in this document is the same. Appropriately substituted aniline halogenous using ICl, I2or Br2and then Amin protect in the form of carbamate using, for example, triethylamine and chloroformiate. This aryl halides connect with Alcina containing the appropriate functional groups, using Pd and copper catalysts in the presence of a base such as triethylamine. This resulting product can be subjected to cyclization using Pd catalyst in the presence of allylchloride and replaced oxirane. Then the nitrogen atom of the indole can be alkilirovanii processing strong base, such as sodium bis(trimethylsilyl)amide, n-BuLi, sodium hydride or potassium hydride in a solvent such as DMF, DMSO or THF, followed by reaction with an appropriate halide. Then arylindole you can handle 9-BBN and then palladium catalyst, followed by addition of aryl - or vinylidine for the implementation of combination reaction Suzuki. With the resulting intermediate compounds can remove protection using hydrazine or alkylamine, receiving a primary amine. This amine can then process the necessary sulphonylchloride for two-phase conditions, the mixture of aqueous sodium bicarbonate/dichloromethane, or in an organic solvent with addition of a base, representing blocked the amine content of inorganic fillers. The final hydrolysis is carried out under basic conditions with sodium hydroxide in a mixture of water, methanol and THF at room temperature or at elevated temperature. Alternatively, you can split the processing thiamethoxam sodium in a solvent such as THF or DMF, at elevated temperature (50-100°).

Method To

Method To offer an alternative method of preparing compounds according to this invention. Appropriately substituted aniline halogenous using ICl, I2or Br2and then Amin protect as carbamate or amide, using, for example, triperoxonane anhydride, triethylamine and dimethylaminopyridine. This intermediate compound then reacts with Alcina containing the appropriate functional groups, using Pd and copper catalysts in the presence of a base. The resulting arylalkyl subjected to cyclization to indoles, by heating with an amine, such as piperidine. To obtain the protected amine using standard reaction conditions Mitsunobu, phosphine, azodicarboxylate and talmid. Indole can be alkilirovanii in C3 position (position 3 carbon atom of the indole) aldehydes or the corresponding acetals in the presence of a Lewis acid or Bronsted, such as Ateret of boron TRIFLUORIDE or triperoxonane acid. Then the volume of the indole nitrogen can be alkilirovanii processing strong base, such as sodium bis(trimethylsilyl)amide, n-BuLi, sodium hydride or potassium hydride, in a solvent such as DMF, DMSO or THF, followed by reaction with an appropriate halide. With the resulting intermediate compounds can remove protection using hydrazine or alkylamine, resulting in obtaining a primary amine. This amine can then process the necessary sulphonylchloride for two-phase conditions, the mixture of aqueous sodium bicarbonate/dichloromethane, or in an organic solvent with addition of a base, representing a blocked organic amine. The final hydrolysis is carried out under basic conditions with sodium hydroxide in a mixture of water, methanol and THF at room temperature or at elevated temperature.

Alternatively, you can split the processing thiamethoxam sodium in a solvent such as THF or DMF, at elevated temperature (50-100°).

Method L

Method L offers another alternative method of preparing compounds according to this invention. Accordingly aniline substituted with halogen, see methods J and K, and symmetric alkanol or alkenol with one protective group, for example, secure TPR, interacts in the presence of a base, copper and palladium catalysts, followed by removing the protecting what s under acidic conditions, when using a substrate with one protective group, giving a symmetric indolyl. Remove symmetry with diol processing carbonyl diimidazol in an appropriate solvent and then the primary alcohol replaces the standard reaction conditions Mitsunobu, and to obtain the desired ether used phosphine, azodicarboxylate and alcohol. The carbamate can be expanded by interaction with sodium azide to obtain alkylated. The nitrogen atom of the indole you can then alkilirovanii processing strong base, such as sodium bis(gramatically)amide, n-BuLi, sodium hydride or potassium hydride, in a solvent such as DMF, DMSO or THF, followed by interaction with a corresponding halide. Treatment with triphenylphosphine in wet THF gives the desired alkylamine. Then Amin can handle the necessary sulphonylchloride for two-phase conditions, the mixture of aqueous sodium bicarbonate/dichloromethane, or in an organic solvent with addition of a base, representing a blocked organic amine. The final hydrolysis is carried out under basic conditions with sodium hydroxide in a mixture of water, methanol and THF at room temperature or at elevated temperature. Alternatively, the splitting can be done by processing thiamethoxam sodium in a solvent such as THF or DMSO, when the high is the temperature value (50-100° C).

Method M

When Z=NHSO2X1R1

When Z=NH2

When Z=HE

Method M provides further strategy to obtain compounds according to this invention. Appropriately substituted aniline halogenous using ICl, I2or Br2and then the amine can be alkilirovanii using an organic base and a halide. Thus obtained alkylamine then subjected to interaction with the use of a palladium catalyst in the presence of a source of chloride and base with phosphine or without a phosphine and necessary Alcina getting indole. When Z in alkene is a NHSO2(CH2)n2X1R1synthesis finish by hydrolysis under basic conditions with sodium hydroxide in a mixture of water, methanol and THF at room temperature or at elevated temperature. Alternatively, the splitting can be done by processing thiamethoxam sodium in a solvent such as THF or DMSO, at elevated temperature (50-100°).

When Z=NH2

The resulting indole you can then process the necessary sulphonylchloride for two-phase conditions, the mixture of aqueous sodium bicarbonate/dichloromethane, and the organic solvent with addition of a base, representing a blocked organic amine. The final hydrolysis is carried out under basic conditions with sodium hydroxide in a mixture of water, methanol and THF at room temperature or at elevated temperature. Alternatively, the splitting can be done by processing thiamethoxam sodium in a solvent such as THF or DMSO, at elevated temperature (50-100°).

When Z=HE

The resulting alcohol can be converted to a halide or mesilate, for example, using methanesulfonanilide and organic base, which then could be replaced by sodium azide in DMF. The resulting alkylated can be restored under the action of triphenylphosphine and wet THF. Amin can be sulfonylureas action sulphonylchloride for two-phase conditions SCHOTT and Bauman, the mixture of aqueous bicarbonate and dichloromethane, or in anhydrous conditions, in the presence of dichloromethane and the organic base such as N,N-diisopropylethylamine. The resulting intermediate compound hydrolyzing using the base, NaOH, KOH, LiOH and a mixture of solvents, including alcohol, water, and tetrahydrofuran.

Method N

Method N offers a further strategy to obtain subgroup of compounds according to this invention. 2-Formylindole with the functional group of the C3 position (see method A) interacts with the reaction conditions of the Wittig or other conditions of ORGANOMETALLIC reactions, leading to formation of ester of alkanoate. This ester can be converted to the acid treatment of Pd, and the resulting unsaturated acid restores the hydrogenation. Akilova acid activated by conversion to the acid chloride by the action of oxalicacid or floramite through lanehead and then processed with the proper borhydride reducing agent, getting the alcohol. Alcohol is converted to the bromide using triphenylphosphine and chetyrehhloristy carbon, and then replace the anion sulfonamida obtained by processing primary sulfonamida strong base, such as NaH, n-BuLi, etc. getting the desired secondary sulfonamide. The resulting intermediate compound, which represents an ester, hydrolyzing using the base, NaOH, KOH, LiOH and a mixture of solvents, including alcohol, water, and tetrahydrofuran.

Example 142: 4-[2-(1-benzhydryl-2-{3-[(benzylmethyl)amino]propyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: In a 250 ml of tetrahydrofuran at room temperature dissolve 5.0 g of methyl ester 4-[2-(1-benzhydryl-2-formyl-1H-indol-3-yl)ethoxy]benzoic acid, stage 4, example 1 (0,0092 M, 1 EQ.) and 5.0 g of allyl(triphenylphosphonium)acetate (0,M, 1.5 EQ.). The pale yellow solution is stirred for one hour. TLC shows a new spot at Rf+0.5 V mixture of 1:1 hexane/ethyl acetate and the absence of a source of indole. The reaction mixture is poured into 500 ml of ethyl acetate, washed with water (2×125 ml) and saturated salt solution (2×125 ml). The organic layer is dried over magnesium sulfate and filtered. The filtrate is evaporated to a yellow oily substance, which was dissolved in 50 ml of a mixture 1:1 hexane/ethyl acetate and filtered through a layer of silica gel to remove the base material. Get 5,23 g of methyl ester of 4-{2-[2-(2-allyloxycarbonyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoic acid as a yellow oily substance (yield 91%).

Stage 2: To 75 ml of THF added 6,12 g of methyl ester of 4-{2-[2-(2-allyloxycarbonyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoic acid (0,098 M, 1 EQ.) and 1.12 g of tetrakis(triphenylphosphine)palladium (0) (0.001 M, 0.1 EQ.). To the reaction mixture dropwise over 20 min add at 8.60 ml of the research (0,098 M, 1 EQ.). After complete addition, the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture is poured into 250 ml of ethyl acetate and the organic solution is extracted with 1 N. NaOH (2×75 ml). The aqueous layers are combined and acidified with 1 N. HCl, the acidic solution is extracted with ethyl acetate (3×75 ml). The organic layers are combined and about is to see a saturated salt solution (1× 50 ml), dried over magnesium sulfate, filtered and evaporated, obtaining the methyl ester of 4-{2-[1-benzhydryl-2-(2-carboxyvinyl)-5-chloro-1H-indol-3-yl]ethoxy}benzoic acid as a yellow oily substance (of 5.40 g, yield 97%).

Stage 3: In 15 ml of methanol was dissolved 400 mg of methyl ester of 4-{2-[1-benzhydryl-2-(2-carboxyvinyl)-5-chloro-1H-indol-3-yl]ethoxy}benzoic acid (0,0007 M, 1 EQ.). To this solution was added 80 mg of 5% platinum on charcoal in suspension in 5 ml of methanol. The black suspension was placed in an atmosphere of hydrogen via a balloon and stirred for 24 hours at room temperature. Hydrogen is pumped out, add 80 mg of 5% platinum on charcoal in 5 ml of methanol and the reaction mixture is again placed in an atmosphere of hydrogen via a balloon and stirred for additional 24 hours at room temperature. The reaction control NMR and in the moment, celebrate the full conversion. The reaction mixture was filtered through celite and the filtrate is evaporated, obtaining the methyl ester of 4-{2-[1-benzhydryl-2-(2-carboxyethyl)-5-chloro-1H-indol-3-yl]ethoxy}benzoic acid in the form of hard yellow-green substance (320 ml, yield 79%).

Stage 4: In 1.0 ml of anhydrous methylene chloride was dissolved 100 mg of methyl ester of 4-{2-[1-benzhydryl-2-(2-carboxyethyl)-5-chloro-1H-indol-3-yl]ethoxy}benzoic acid (is 0.0002 M, 1 EQ.). The solution to ablaut of 33.5 mg oxalicacid (0,0003 M, 1.5 EQ.) and the reaction mixture is stirred for one hour at room temperature. Then the reaction mixture is evaporated until dry and the residue is dissolved in 1.0 ml anhydrous ethyl ether, to which is added 0,027 ml of TMEDA. To this solution was added 0.35 ml of a solution of zinc borohydride in a simple ester, prepared by the literature method (Tet. Lett. Vol.22, pg.4723, 1981). The reaction mixture was stirred for 15 min at room temperature and quenched with 1.0 ml of water. The reaction mixture was diluted with 10 ml of ethyl ether and the aqueous layer was separated, the organic layer is dried over magnesium sulfate, filtered and evaporated to obtain a transparent oily substance. The oily substance is subjected to chromatography using a mixture of ethyl acetate/hexane (1:9)to give methyl ester of 4-{2-[1-benzhydryl-5-chloro-2-(3-hydroxypropyl)-1H-indol-3-yl] ethoxy}benzoic acid as a white foam (81 mg, yield 83%).

Stage 5: In 2.0 ml of anhydrous methylene chloride was dissolved 104,0 mg methyl ester 4-{2-[1-benzhydryl-5-chloro-2-(3-hydroxypropyl)-1H-indol-3-yl]ethoxy}benzoic acid (is 0.0002 M, 1.0 EQ.). To this solution add 116,0 mg-linked polystyrene triphenylphosphine (1,61 mmol/g, is 0.0002 M, 1.0 EQ.), then add 125,0 mg chetyrehpostovye carbon (0,0004 M, 2 EQ.). The suspension is stirred for 2 hours at room Tempe is the atur, then the reaction mixture is filtered and the filtrate evaporated to an orange oily substance. The oily substance is purified column chromatography using a mixture of ethyl acetate/hexane (2:98)to give 100 mg (86%) of methyl ester of 4-{2-[1-benzhydryl-2-(3-bromopropyl)-5-chloro-1H-indol-3-yl]ethoxy}benzoic acid as a yellow foam.

Stage 6: In 0.5 ml of DMF is dissolved 33.3 mg-toluensulfonate (is 0.0002 M, 1.2 equiv.) and this mixture was added to a suspension of 8.0 mg of 60% sodium hydride (is 0.0002 M, 1.2 equiv.) in 0.5 ml of DMF. The reaction mixture was stirred for 30 min, then was added 100 mg of methyl ester of 4-{2-[1-benzhydryl-2-(3-bromopropyl)-5-chloro-1H-indol-3-yl]ethoxy}benzoic acid (is 0.0002 M, 1.0 EQ.) in 0.5 ml of DMF and the solution is stirred for an additional hour. The reaction mixture was quenched with water and diluted with 10 ml of ethyl acetate. The organic layer was washed with water (2×5 ml) and a saturated solution of salt (2×5 ml), dried over magnesium sulfate and evaporated to a yellow oily substance. The residue is purified column chromatography (ethyl acetate/hexane 5:95)to give 20 mg (17%) of methyl ester of 4-{2-[1-benzhydryl-5-chloro-2-(3-phenylmethanesulfonyl)-1H-indol-3-yl]ethoxy}benzoic acid as a transparent oily substance.

Stage 7: 20.0 mg of indole from example 6 (0,00002 M, 1 EQ.) hydrolyzing, as in example 1, step 8, receiving specified in zag is lowke connection (13,0 mg, yield 88%). m/z (M-1) 691.

Method About

Appropriately substituted halogenated communicates with the corresponding halide and tertiary aminoven base, giving N-alkilirovanny substrate for the reaction of a combination of Changesare (Akinola in the presence of Pdiiand relevant grounds). Arylalkyl subjected to cyclization to indoles under the action of a halide of copper and heat. Free alcohol protecting silyl protecting group, interacting with similiarites in the presence of a base such as imidazole. This indol then subjected C3 to acylation, interacting with the appropriate acid chloride, and the resulting connection restore strong reducing agents, preferably borane or a complex of borane. Then the primary alcohol is oxidized to aldehyde by any oxidant, including oxalicacid/DMSO (conditions Swarna) or TPAP/NMO. This aldehyde is subjected to the conditions of reductive amination, which include borhydride the reducing agent and, in some cases, protonotariou acid and a primary or secondary amine. Then silyl ether is removed protection fluoride source, including CsF, TBAF, HF, etc. This free convert alcohol into a leaving group, Gal is genid, using CBr4and phosphine, or sulphonate ester by methanesulfonanilide and tertiary amine. Interact activated alcohol with sodium azide in DMF or DMSO, getting the desired azide, which, in turn, restore under conditions of Staudinger, a phosphine and a mixture of THF/N2O, or by hydrogenation using hydrogen and an appropriate catalyst. Amin can be sulfanilamide under the action of sulphonylchloride for two-phase conditions SCHOTT and Bauman, the mixture of aqueous bicarbonate and dichloromethane, or in anhydrous conditions, in the presence of dichloromethane and the organic base such as N,N-diisopropylethylamine. The resulting intermediate compound hydrolyzing using the base, NaOH, KOH, LiOH and a mixture of solvents, including alcohol, water, and tetrahydrofuran.

In the following examples, 143-151 synthesis carried out using the method of N.

Example 143: 4-{[2-(1-benzhydryl-2-{2-[(benzylmethyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethyl]amino}benzoic acid

Step 1: To a solution of 4-chloro-2-joanina (16.5 g, a total of 65.1 mmol) in DMF (250 ml) at room temperature add α-bromodiphenylmethane (21,5 g, and 84.6 mmol) andfromPr2NEt (23 ml, 130 mmol) and the reaction mixture is heated at 45°With during the night. After removal under reduced pressure Le is ucih components, the residue is dissolved in EtOAc, washed with water (3×), saturated salt solution and dried over MgSO4. Purification by chromatography on a column with SiO2(hexane a mixture of 5% EtOAc/hexane) gives the desired benzhydryl-(4-chloro-2-itfinal)Amin (26,1 g, yield 97%) as a yellowish solid substance.

Stage 2: a Mixture of benzhydryl-(4-chloro-2-itfinal)amine (26,1 g, 62,2 mmol), PdCl2(PPh3)2(1.90 g, to 2.67 mmol), CuI (1.2 g, 6.2 mmol), 3-buten-1-ol and Et3N (120 ml) was stirred at 45°C for 20 hours. The reaction mixture was filtered through celite and washed with EtOAc. The filtrate is concentrated and re-dissolved in EtOAc, washed with water (3×), saturated salt solution and dried over MgSO4. The crude 4-[2-(benzylamino)-5-chlorophenyl]but-3-in-1-ol (25,5 g) directly used in the next stage without additional purification.

Stage 3: a Solution of the crude 4-[2-(benzylamino)-5-chlorophenyl]but-3-in-1-ol (25,5 g) and CuI (2.7 g, 14.1 mmol) in DMF (200 ml) is heated at 125°C for 24 hours. The reaction mixture was filtered through celite and washed with EtOAc. The filtrate is concentrated and re-dissolved in EtOAc, washed with water (3×), saturated salt solution and dried over MgSO4. Chromatography on a column of silica gel (30% EtOAc/hexane) gives the desired 2-(1-benzhydryl-5-chloro-1H-indol-2-yl)ethanol in the form of a yellow solid substance (14.5 g, yield 73% over two stages).

Stage 4: To a solution of 2-(1-benched the Il-5-chloro-1H-indol-2-yl)ethanol (15.3 g, of 42.3 mmol) in CH2Cl2(190 ml) at 0°With add imidazole (3,72 g, 55,0 mmol) and TBDPSCl (13,2 ml, 50.8 mmol). After stirring at the same temperature for 1.5 hours the reaction mixture is washed with cold water (3×), saturated salt solution and dried over MgSO4. The crude silyl ether directly used in the next stage without additional purification.

Stage 5: To a solution of the crude silyl ether in Et2O (200 ml) at 0°With added dropwise oxalicacid (4,84 ml of 55.5 mmol). The reaction mixture is allowed to warm to room temperature and stirring is continued for 4 hours, then add Et3N (35 ml) and Meon (10 ml). The mixture is washed with water, saturated salt solution and dried over MgSO4. Raw ketoester directly used in the next stage.

Stage 6: metafire in THF (300 ml) at room temperature is added dropwise NR3·IU2S (10 M, 36 ml) and the reaction mixture refluxed overnight. The mixture is cooled to 0°With, then add NaOH (30%, 150 ml) and stirring continued for 30 min THF is removed under reduced pressure and the reaction mixture is extracted with EtOAc, washed with water, saturated salt solution and dried over MgSO4. Purification of column chromatography (15 to 20% EtOAc/hexane) gives the desired product is CT in the form of a white solid (15.9 g, of 24.7 mmol, 58% for the three stages).

Step 7: To a solution of oxalicacid (0,372 ml, 4,27 mmol) in CH2Cl2(10 ml) at -78°With added dropwise DMSO (0,661 ml, 9,31 mmol). The reaction mixture was stirred at the same temperature for 5 minutes, then add a solution of 2-{1-benzhydryl-2-[2-(tert-butyldiphenylsilyl) ethyl]-5-chloro-1H-indol-3-yl}ethanol (2.50 g, 3.88 mmol) in CH2Cl2(8 ml). After an additional 40 min stirringfromPr2NEt (3,38 ml of 19.4 mmol), the reaction mixture is quenched with cold water (5 ml) and extracted with CH2Cl2. The organic layer is dried over MgSO4and evaporated. The crude {1-benzhydryl-2-[2-(tert-butyldiphenylsilyl)ethyl]-5-chloro-1H-indol-3-yl}acetaldehyde directly used in the next stage.

Step 8: To a solution of the crude aldehyde (3.88 mmol) in 1,2-dichloroethane (39 ml) at 0°With added methyl 4-aminobenzoate (645 mg, 4,27 mmol), acetic acid (1,33 ml) and NaBH(SLA)3. The reaction mixture is allowed to warm to room temperature overnight and quenched with cold NaHCO3. Processing extraction will give the desired methyl ester 4-(2-{1-benzhydryl-2-[2-(tert-butyldiphenylsilyl)ethyl]-5-chloro-1H-indol-3-yl}ethylamino)benzoic acid, which is directly used in the next stage without additional purification.

Step 9: methyl ether of 4-(2-{1-benzo who idril-2-[2-(tert-butyldiphenylsilyl)ethyl]-5-chloro-1H-indol-3-yl}ethylamino)benzoic acid (3.88 mmol) in THF (25 ml) at 0° To add a mixture SPLA:1M TBAF (in THF) (2,3 ml:5.8 ml) and the reaction mixture was stirred at room temperature for 18 hours. Processing extraction, followed by rubbing in a mixture of 5% EtOAc/hexane to give the desired methyl ester 4-{2-[1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethylamino]benzoic acid, with a small admixture, in the form of a solid off-white substance (92%, for the three stages).

Step 10: To a solution of methyl ester 4-{2-[1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethylamino]benzoic acid (1.64 g, 3.04 from mmol) in CH2Cl2when 0°add Et3N (0,636 ml, 4,56 mmol) and MsCl (0,282 ml of 3.64 mmol). After stirring at the same temperature for 35 min, the reaction mixture was quenched with cold water. Processing extraction gives the crude mesilate in the form of a solid off-white substance (1.70 g, 90%).

Stage 11: a Solution of the crude nelfinavir (1.70 g, a 2.75 mmol) and NaN3(89 mg, of 13.8 mmol) in DMF (14 ml) was stirred at 80°C for 6 hours. The reaction mixture was diluted with EtOAc and treated with water, followed by column flash chromatography, obtaining the desired methyl ester 4-{2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethylamino]benzoic acid (813 mg, yield 52%).

Step 12: To the methyl ether of 4-{2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethylamino]benzoic acid (400 mg, 0,709 mmol) in TG is (4 ml) at 0° With the parts add Ph3R (223 mg, 0,851 mmol). The reaction mixture was stirred at room temperature for 11 hours and 35°C for 4 h, after which water is added (50 μl) and stirring is continued over night. The reaction mixture was diluted with EtOAc, dried over MgSO4and clear column flash chromatography (EtOAc mixture to 20% MeOH/EtOAc with 1% Et3N), obtaining the desired methyl ester 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethylamino]benzoic acid (201 mg, 53%) as a solid.

Stage 13: the Intermediate connection of stage 12 handle α-toluensulfonate procedure of example 87, step 2, obtaining the desired product with a yield of 72%.

Stage 14: the Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 87%. MS high resolution calc. for [C39H36Cl2N3O4S+N] 678,21879 found 678,2178.

Example 144: 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chloro-6-were)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}amino)benzoic acid

Stage 1: the Intermediate compound from example 143, step 12 is treated with 2-chloro-6-methylbenzenesulfonamide the procedure described in example 87, step 2, obtaining the desired product with a yield of 85%.

Stage 2: Intermediate connection of t is engaged in a complex ether, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 96%. MS high resolution calc. for [C39H35Cl2N3O4S+N] 712,17981 found 712,17895.

Example 145: 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-methoxyphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}amino)benzoic acid

Stage 1: the Intermediate compound from example 143, step 12 process 2-methoxybenzenesulfonamide the procedure described in example 87, step 2, obtaining the desired product with a yield of 85%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 92%. MS high resolution calc. for [C39H36Cl3O5S+N] 694,2137 found 694,21311.

Example 146: 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}amino)benzoic acid

Stage 1: the Intermediate compound from example 143, step 12 process 2-chlorobenzenesulfonamide the procedure described in example 87, step 2, obtaining the desired product with a yield of 21%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 94%. MS high resolution calc. for [C38H3 Cl2N3O4S+N] 698,16416 found 698,16365.

Example 147: 4-[[2-(1-benzhydryl-2-{2-[(benzylmethyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethyl](methyl)amino]benzoic acid

Stage 1: Crude {1-benzhydryl-2-[2-(tert-butyldiphenylsilyl)ethyl]-5-chloro-1H-indol-3-yl}acetaldehyde stage 7 of example 143 treated with methyl ether 4-methylaminoethanol acid by the procedure described in example 143, step 8, receiving the desired methyl ester 4-[(2-{1-benzhydryl-2-[2-(tert-butyldiphenylsilyl)ethyl]-5-chloro-1H-indol-3-yl}ethyl)methylamino]benzoic acid with a yield of 73%.

Stage 2: Given the title compound is prepared by the procedure described in example 143, step 9. The crude methyl ester of 4-({2-[1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethyl]methylamino]benzoic acid directly used in the next stage without additional purification.

Stage 3-6: Methyl ester of 4-({2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl]methylamino]benzoic acid obtained by the procedure described in example 143, the stage 10-12 exit 61% (for stage 3).

Step 7: a Solution of methyl ester 4-({2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl]methylamino]benzoic acid (410 mg, 0,709 mmol) and 10% Pd/C (155 mg) in a mixture of MeOH/CH2Cl2(7 ml:1 ml) is stirred in an atmosphere of H2(1 ATM) for 2 hours 15 minutes the Reaction mixture is filtered is through celite and washed with Meon and CH 2Cl2. Column flash chromatography of the residue (CH2Cl2up to 8% MeOH/CH2Cl2) gives the desired methyl ester of 4-({2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl]methylamino]benzoic acid with a yield of 78% (305 mg).

Stage 8: the Intermediate connection of stage 7 process α-toluensulfonate the procedure described in example 87, step 2, obtaining the desired product with a yield of 83%.

Stage 9: the Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 91%. MS high resolution calc. for [C39H38ClN3O4S+N] 692,23444 found 692,23374.

Example 148: 4-[{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}(methyl)amino]benzoic acid

Stage 1: the Intermediate compound from example 147, step 7 is treated with 3,4-dichlorobenzotrifluoride the procedure described in example 87, step 2, obtaining the desired product with a yield of 87%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 68%. MS high resolution calc. for [C40H36Cl3N3O4S+N] 760,15649 found 760,1573.

Example 149: 4-[{2-[1-benzhydryl-chlor-2-(2-{[(2-chloro-6-were)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}(methyl)amino]benzoic acid

Stage 1: the Intermediate compound from example 147, step 7 is treated with 2-chloro-6-methylbenzenesulfonamide the procedure described in example 87, step 2, obtaining the desired product with a yield of 96%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 88%. MS high resolution calc. for [C40H37Cl2N3O4S+N] 726,19546 found 726,19461.

Example 150: 4-[{2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}(methyl)amino]benzoic acid

Stage 1: the Intermediate compound from example 147, step 7 process 2-chlorobenzenesulfonamide the procedure described in example 87, step 2, obtaining the desired product with a yield of 96%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 84%. MS high resolution calc. for [C39H35Cl3N3O4S+N] 712,17981 found 712,17966.

Example 151: 4-[{2-[1-benzhydryl-5-chloro-2-(2-{[(2-methoxyphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}(methyl)amino]benzoic acid

Stage 1: the Intermediate compound from example 147, step 7 process 2-methoxybenzenesulfonamide procedure description the Noah in example 87, stage 2, obtaining the desired product with a yield of 95%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 73%. MS high resolution calc. for [C40H38ClN3O5S+H] 708,22935 found 708,2286.

Example 152: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,4-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) is added 2,4-dichlorobenzenesulfonyl procedure of example 1, step 7, when receiving the product with the release of 95%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 77%. MS high resolution calc. for C39H33Cl3N2O4S 730,1227 found (ERI+) 731,1299.

Example 153: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) is added 2,6-dichlorobenzenesulfonate procedure of example 1, step 7, when receiving the product with the release of 93%.

Stage 2: Intermediate connection representing an ester, g is koliseum in accordance with the stage 8 of example 1, getting found on the title acid with 71%yield. MS high resolution calc. for C39H33Cl3N2O4S 730,1227 found (ERI+) 731,13005.

Example 154: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,4,6-trichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add 2,4,6-trichlorobenzaldehyde procedure of example 1, step 7, when receiving the product yield 76%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 84%. MS high resolution calc. for C39H32Cl4N2O4S 764,0837 found (ERI+) 765,08981.

Example 155: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-cyanophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add 2-cyanobenzenesulfonyl procedure of example 1, step 7, when receiving the product yield of 87%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1 and purified preparative HPLC, receiving specified in the header of the acid with a yield of 8%. MS high resolution calc. DL is 40H34ClN3O4S 687,1959 found (ERI+) 688,2019.

Example 156: 4-(3-{2-[2-({[2-(aminomethyl)phenyl]sulfonyl}amino)ethyl]-1-benzhydryl-5-chloro-1H-indol-3-yl}propyl)benzoic acid

Stage 1: Methyl 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-cyanophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoate (example 154, step 1, of 0.43 g, 0.61 mmol) dissolved in THF (4 ml) and Meon (12 ml). Add cobalt chloride (II) (0.16 g, 1.2 mmol) and NaBH4(0,23 g, 6.1 mmol). After 2 hours the mixture is filtered, concentrated and subjected to chromatography on silica gel (Meon-CH2Cl2), receiving aminoether with the release of 13%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 59%. MS high resolution calc. for C39H36ClN3O5S 693,2064 found (ERI+) 694,21261.

Example 157: 4-[3-(1-benzhydryl-2-{2-[(1,1'-biphenyl-2-ylsulphonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)propyl]benzoic acid

Stage 1: 2-Bromodiphenyl (with 0.55 ml, 3.2 mmol) dissolved in THF (10 ml) and Et2O (10 ml) and cooled to -78°With, at the same time rapidly dropwise adding n-BuLi (1.3 ml, 2.5 M solution in hexane, 3.2 mmol). After 40 min the mixture was added via cannula to a cooled to -78°With the solution SO2(10 ml) in Et2O (20 ml). The mixture is heated to room temperature over night, the con is intronaut and pound in Et 2O. the resulting white solid is suspended in hexane (40 ml) and cooled to 0°C. Add sulfurylchloride (3.4 ml of 1.0 M solution in CH2Cl2, 3.4 mmol) and the mixture is stirred at room temperature for 5 hours. Then her focus, getting 2-diphenylsulfone with the release of 67%.

Stage 2: methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add 2-biphenylmethanol procedure of example 1, step 7, when receiving the product yield 83%.

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 98%. MS high resolution calc. for C45H39ClN2O4S 738,2319 found (ERI+) 739,23825.

Example 158: 4-{3-[1-benzhydryl-2-(2-{[(2-bromophenyl)sulfonyl]amino}ethyl)-5-chloro-1H-indol-3-yl]propyl}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add 2-bromobenzonitrile procedure of example 1, step 7, when receiving the product yield 76%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 95%. MS high resolution calc. [With 39H34BrClN2O4S+N] 740,1111 found (ERI+) 741,11696.

Example 159: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,4-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 2,4-dichlorobenzenesulfonyl procedure of example 1, step 7 exit 83%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 80%. MS high resolution calc. for C38H31Cl3N2O5S 732,1019 found (ERI+) 733,10824.

Example 160: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 2,6-dichlorobenzenesulfonate procedure of example 1, step 7 exit 77%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 82%. MS high resolution calc. for C38H31Cl3N2O5S 732,1019 found (ERI+) 733,10836.

Example 161: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,4,6-dichlorphenol)sulfonyl]amino}ethyl)-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 2,4,6-trichlorobenzaldehyde procedure of example 1, stage 7 with the release of 90%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 87%. MS high resolution calc. for C38H30Cl4N2O5S 766,0630 found (ERI+) 767,07063.

Example 162: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-cyanophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 2-cyanobenzenesulfonyl procedure of example 1, stage 7 with the release of 82%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1 and purified preparative HPLC, receiving specified in the header of the acid with a yield of 17%. MS high resolution calc. for C39H32ClN3O5S 689,1751; found (ERI+) 690,18082.

Example 163: 4-(2-{2-[2-({[2-(aminomethyl)phenyl]sulfonyl}amino)ethyl]-1-benzhydryl-5-chloro-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: Methyl 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-cyanophenyl)sulfonyl]amino}ethyl)-1H-in the ol-3-yl]ethoxy}benzoate (example 161, stage 1, 0.31 g, 0.44 mmol) dissolved in THF (4 ml) and Meon (12 ml). Add cobalt chloride (II) (0.11 g, 0.88 mmol) and NaBH4(0.17 g, 4.4 mmol). After 2 hours the mixture is filtered, concentrated and subjected to chromatography on silica gel (Meon-CH2Cl2), receiving aminoether with the release of 17%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 39%. MS high resolution calc. for C39H36ClN3About5S 693,2064 found (ERI+) 694,21261.

Example 164: 4-[2-(1-benzhydryl-2-{2-[(1,1'-biphenyl-2-ylsulphonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: the Sulfonamide obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 2-diphenylsulfone (stage 1, the example 156) by the procedure of example 1, stage 7 with the release of 93%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 94%. MS high resolution calc. for C44H37ClN2O5S 740,2112 found (ERI+) 741,21709.

Example 165: 4-{2-[1-benzhydryl-2-(2-{[(2-bromophenyl)sulfonyl]amino}ethyl)-5-chloro-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-what aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 2-bromobenzaldehyde procedure of example 1, stage 7 with the release of 90%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 91%. MS high resolution calc. for C38H32BrClN2O5S 742,0904 found (ERI+) 743,09697.

Example 166: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(5-chloro-2,4-differenl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: To the methyl 4-{3-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) is added 5-chloro-2,4-differentialalgebraic procedure of example 1, step 7, when receiving the product yield 68%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 44%. MS high resolution calc. for [C39H32Cl2F2N2O4S+N] 733,15007 found 733,14978.

Example 167: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-methoxy-4-were)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: To the methyl 4-{3-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add 2-methoxy-4-methylbenzenesulfonamide procedure of example 1, step 7, when receiving the product yield of 86%.

With the adiya 2: Intermediate connection, representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 39%. MS high resolution calc. for [C41H-39ClN2O5S+N] 707,2341 found 707,23407.

Example 168: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(4-chloro-2,5-differenl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: To the methyl 4-{3-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) is added 4-chloro-2,5-differentialalgebraic procedure of example 1, step 7, when receiving the product yield 79%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 63%. MS high resolution calc. for [C39H32Cl2F2H2O4S+N] 733,15007 found 733,14882.

Example 169: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(5-chloro-2,4-differenl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 5-chloro-2,4-differentialthreshold procedure of example 1, step 7, when receiving the product with 38%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 PR is a measure 1, receiving specified in the header of the acid with a yield of 31%. MS high resolution calc. for [C38H30Cl2F2N2O5S+N] 735,12933 found 735,12824.

Example 170: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(4-chloro-2,5-differenl)sulfonyl]amino}ethyl)-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 4-chloro-2,5-differentialthreshold procedure of example 1, step 7 exit 79%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 63%. MS high resolution calc. for [C38H30Cl2F2N2O5S+N] 735,12933 found 735,12913.

Example 171: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-methoxy-4-were)sulfonyl]amino}ethyl)-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 2-methoxy-4-methylbenzenesulfonamide procedure of example 1, step 7.

Stage 2: the Crude intermediate compound, which represents an ester, hydrolyzing in accordance with the stage 8 of example 1, getting 407 mg indicated in the title acid in quantitative yield the m MS high resolution calc. for [C40H37ClN2O6S+N] 709,21337 found 709,21194.

Example 172: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(7-chloro-2,1,3-benzoxadiazole-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) is added 4-chloro-7-chlorosulfonyl-2,1,3-benzoxadiazole procedure of example 1, step 7, when receiving the product with the release of 43%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with the release of 26% after HPLC separation. MS high resolution calc. for [C39H32Cl2N4O5S+N] 739,15433 found 739,1537.

Example 173: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(7-methoxy-2,1,3-benzoxadiazole-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl}propyl)benzoic acid

Stage 1: To the methyl 4-{3-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add 7 methoxybenzo[1,2,5]oxadiazol-4-sulphonylchloride procedure of example 1, step 7, when receiving the product with the release of 43%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 36% after HPLC separation. MS high resolution you the Lis. for [C40H35ClN4O6S+N] 735,2046 found 735,2029.

Example 174: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(7-chloro-2,1,3-benzoxadiazole-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 4-chloro-7-chlorosulfonyl-2,1,3-benzoxadiazole procedure of example 1, stage 7 with the release of 56%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header acid with 30% yield after HPLC separation. MS high resolution calc. for [C36H30Cl2N4O6S+N] 741,1343 found 741,1328.

Example 175: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(7-methoxy-2,1,3-benzoxadiazole-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 4-chloro-7-chlorosulfonyl-2,1,3-benzoxadiazole procedure of example 1, stage 7 with the release of 56%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 36% after HPLC separation. MS high resolution calc. for [C39H33ClN 4O7S+N] 737,1838 found 737,1819.

Example 176: 4-(3-{1-benzhydryl-5-chloro-2-[2-({[5-(2-methyl-1,3-thiazol-4-yl)Tien-2-yl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add 5-(2-methyl-1,3-thiazol-4-yl)thiophene-2-sulphonylchloride procedure of example 1, step 1, getting the product yield of 90%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 100%. MS high resolution calc. for [C41H36ClN3O4S3+H] 766,1636 found 766,1629.

Example 177: 4-(2-{1-benydril-5-chloro-2-[2-({[5-(2-methyl-1,3-thiazol-4-yl)Tien-2-yl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 5-(2-methyl-1,3-thiazol-4-yl)thiophene-2-sulphonylchloride procedure of example 1, stage 7 with the release of 100%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 92%. MS high resolution calc. for [C40H34ClN3O5S3-N] 767,1269 found 766,1259.

Example 178: 4-[2-(-benzhydryl-5-chloro-2-{2-[(Tien-3-ylsulphonyl}amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 3-thiophenesulfonyl procedure of example 1, stage 7 with the release of 91%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 96%. MS high resolution calc. for [C36H31ClN2O5S2+H] 671,14357 found 671,1428.

Example 179: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(6-morpholine-4-espiridion-3-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 6-morpholino-3-pyridinesulfonamide procedure of example 1, stage 7 with the release of 91%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 92%. MS high resolution calc. for [C41H-39ClN4O6S+N] 751,23516 found 751,2345.

Example 180: 4-[3-(1-benzhydryl-5-chloro-2-{2-[(Tien-3-ylsulphonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add 3-thiopental eilhard procedure of example 1, stage 7, when receiving the product yield of 87%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 99%. MS high resolution calc. for [C37H33ClN2O4S2+H] 669,16431 found 669,1629.

Example 181: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(6-morpholine-4-espiridion-3-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add 6 morpholino-3-pyridinesulfonamide procedure of example 1, step 7, when receiving the product yield 79%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 89%. MS high resolution calc. for [C42H41ClN4O5S+N] 749,2559 found 749,255.

Example 182: 4-(2-{1-benzhydryl-2-[2-(benzo[1,2,5]oxadiazol-4-sulfonylamino)ethyl]-5-chloro-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and isoxazol[4,5-C]pyridine-4-sulphonylchloride procedure of example 1, stage 7 with the release of 88%.

Stage 2: Intermediate connection representing the Wallpaper ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 94%. MS high resolution calc. for [C38H31ClN4O6S+N] 707,17256 found 707,1719.

Example 183: 4-(3-{1-benzhydryl-2-[2-(benzo[1,2,5]oxadiazol-4-sulfonylamino)ethyl]-5-chloro-1H-indol-3-yl)propyl]benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add benzofuran-4-sulphonylchloride procedure of example 1, step 1, getting the product yield 69%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 93%. MS high resolution calc. for [C39H33ClN4O5S2+H] 705,1933 found 705,1931.

Example 184: 4-(2-{1-benzhydryl-2-[2-(2-benzyloxycarbonylamino)ethyl]-5-chloro-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 2-benzyloxybenzaldehyde procedure of example 1, step 7 exit 87%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 95%. MS high p is resheniya calc. for [C45H39ClN2O6S-N] 769,21446 found 769,2129.

Example 185: 4-(2-{1-benzhydryl-5-chloro-2-[2-(2-isopropoxybenzonitrile)ethyl]-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 2-isopropoxybenzonitrile procedure of example 1, stage 7 with the release of 88%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 74% after trituration in diethyl ether. MS high resolution calc. for [C41H39ClN2O6S+N] 723,22902 found 723,2284.

Example 186: 4-(3-{1-benzhydryl-5-chloro-2-[2-(2-isopropoxybenzonitrile)ethyl]-1H-indol-3-yl)propyl]benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add 2-isopropoxybenzonitrile procedure of example 1, step 7, when receiving the product with 71%yield.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 82% after HPLC purification. MS high resolution calc. for [C42H41ClN2O5S+N] 721,24975 found 721,490.

Example 187: 4-(3-{1-benzhydryl-2-[2-(2-benzyloxycarbonylamino)ethyl]-5-chloro-1H-indol-3-yl)propyl]benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add 2-benzyloxybenzophenone procedure of example 1, step 7, when receiving the product with the release of 57%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 97% after HPLC purification. MS high resolution calc. for [C46H41ClN2O5S+N] 769,2505 found 769,2494.

Example 188: 4-(3-{1-benzhydryl-2-[2-(2-hydroxybenzylideneamino)ethyl]-1H-indol-3-yl)propyl]benzoic acid

Step 1: Benzyl group from stage 1 of example 186 is removed by hydrogenolysis. The crude substance is purified on a column of silica gel using CH2Cl2- 5% EtOAc/CH2Cl2with the formation of the mixture, which is further purified HPLC, obtaining the methyl ester of 4-(3-{1-benzhydryl-2-[2-(2-hydroxybenzylideneamino)ethyl]-1H-indol-3-yl)propyl]benzoic acid (7%) and methyl ester of 4-(3-{1-benzhydryl-5-chloro-2-[2-(2-hydroxybenzylideneamino)ethyl]-1H-indol-3-yl)propyl]benzoic acid (18%).

Stage 2: Intermediate connection, which represents a methyl ester of 4-(3-{1-benzhydryl-2-[2-(2-hydroxyben is azulfidinee)ethyl]-1H-indol-3-yl)propyl]benzoic acid, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 81%. MS high resolution calc. for [C39H36N2O5S+N] 645,2418 found 645,2423.

Example 189: 4-(3-{1-benzhydryl-5-chloro-2-[2-(2-hydroxybenzylideneamino)ethyl]-1H-indol-3-yl)propyl]benzoic acid

Stage 1: the Intermediate connection representing a methyl ester of 4-(3-{1-benzhydryl-5-chloro-2-[2-(2-hydroxybenzylideneamino)ethyl]-1H-indol-3-yl}propyl)benzoic acid, from stage 1 of example 188 hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 86%. MS high resolution calc. for [C39H35ClN2O5S+N] 679,2028 found 679,2038.

Example 190: 4-(2-{1-benzhydryl-5-chloro-2-[2-(2-chlorobenzenesulfonamide)ethyl]-1H-indol-3-yl)ethoxy]-2-Formentera acid

Step 1: To a solution of Ph3P (698 mg, 2.7 mmol, 2.0 EQ.) in THF (10 ml) slowly add diisopropylethylamine (0,55 ml, 2.7 mmol, 2.0 EQ.) when 0°C in an atmosphere of N2. The mixture is stirred for 15 minutes a Solution of 2-{1-benzhydryl-2-[2-(tert-butyldiphenylsilyl)ethyl]-5-chloro-1H-indol-3-yl}ethanol (859 mg, 1.3 mmol, 1.0 EQ., stage 6, example 142) in THF (5 ml) is added to the reagents Mitsunobu, followed by adding methyl ester 2-fluoro-4-hydroxybenzoic acid (340 mg, 2.0 mmol, 1.5 EQ.). Obtained the resulting solution is stirred over night. Remove THF. The residue is partitioned between EtOAc and water. The organic phase is washed with water, saturated salt solution and dried over Mg3O4. The product was then purified on a column of silica gel using a mixture of 8% EtOAc/hexane. Obtain 0.95 g (90%) of product as a white solid.

Stage 2: Remove protection from the methyl ester of 4-(2-{1-benzhydryl-2-[2-(tert-butyldiphenylsilyl)ethyl]-5-chloro-1H-indol-3-yl}ethoxy)-2-fermenting acid, following the procedure of example 143, step 9, receiving the methyl ester of 4-{2-[1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethoxy}-2-fermenting acid yield 89%.

Stage 3: Methyl ester of 4-{2-[1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethoxy}-2-fermenting acid activate the conversion mesilate, as described in stage 10 of example 143, and the resulting product is used without purification in the next stage.

Stage 4: Mesilate from the previous step replaces the azide as described in stage 11 of example 143, receiving the methyl ester of 4-{2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}-2-fermenting acid with a yield of 97% (in two stages).

Stage 5: Methyl ester of 4-{2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}-2-fermenting acids restore under conditions of Staudinger, receiving methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}-2-perbenzoate with output is om 93%.

Stage 6: Implement the interaction of methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}-2-perbenzoate from the previous stage with 2 chlorobenzenesulfonamide in accordance with the procedure of example 1, step 7, obtaining the desired product with a yield of 73%.

Stage 7: the Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 96%. MS high resolution calc. for [C38H31Cl2FN2O5S+N] 717,13876 found 717,1365.

Example 191: 4-(2-{1-benzhydryl-5-chloro-2-[2-(2-chloro-6-methylbenzenesulfonamide)ethyl]-1H-indol-3-yl}ethoxy)-2-Formentera acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}-2-perbenzoate (stage 5, example 190) and 2-chloro-6-methylbenzenesulfonamide procedure of example 1, step 7 exit 66%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 95%. MS high resolution calc. for [C39H33Cl2FN2O5S+N] 731,15441 found 731,1532.

Example 192 N-[2-(1-benzhydryl-5-chloro-3-{2-[4-(2H-tetrazol-5-yl)phenoxy]ethyl}-1H-indol-2-yl)ethyl]-1-(3,4-dichlorophenyl)methanesulfonamide

Stage 1: Exercise maintains deistvie 2-{1-benzhydryl-2-[2-(tert-butyldiphenylsilyl)ethyl]-5-chloro-1H-indol-3-yl}ethanol from stage 6 of example 142 4-hydroxybenzonitrile under conditions described in example 189, step 1, receiving 4-(2-{1-benzhydryl-2-[2-(tert-butyldiphenylsilyl)ethyl]-5-chloro-1H-indol-3-yl}ethoxy)benzonitrile with the release of 85%.

Stage 2: Remove protection from silyl ester from the previous step, following the example 143, step 9, receiving 4-{2-[1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethoxy}benzonitrile with the release of 93%.

Stage 3: the Alcohol from the previous stage trigger conversion in mesilate, as described in stage 10 of example 143, getting the desired mesilate, which is used without purification in the next stage.

Stage 4: Mesilate from the previous step is treated under the conditions described in stage 11 of example 143, receiving 4-{2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzonitrile with the release of 91% (in two stages).

Stage 5: 4-{2-[2-(2-Azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzonitrile restore under conditions of Staudinger, as described in detail in stage 12 of example 143, receiving 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzonitrile with the release of 92%.

Stage 6: Implement the interaction of 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzonitrile from the previous stage and (3,4-dichlorophenyl)methanesulfonamide in accordance with the procedure of example 1, step 7, obtaining the desired product with a yield of 92%.

Step 7: a Mixture of nitrile (1.0 EQ.), azidothymidine is on (2.0 equiv.) oxide dibutyrate (0.1 EQ.) and toluene (3.3 ml/mmol) is heated in a sealed tube at 120°C for 20 hours. The mixture is acidified with 1 N. HCl at room temperature, then diluted with EtOAc. The organic phase is washed with water and saturated salt solution, dried over MgSO4. The crude tetrazole subjected to chromatography using a mixture of 50% EtOAc/hexane to 80% EtOAc/hexane plus 0.5% acetic acid, receiving specified in the header of the product with a yield of 58%. MS high resolution calc. for [C39H33Cl3N6About3S+N] 771,14732 found 771,1475.

Example 193 N-[2-(1-benzhydryl-5-chloro-3-{2-[4-(2H-tetrazol-5-yl)phenoxy]ethyl}-1H-indol-2-yl)ethyl]-2-chlorobenzenesulfonamide

Stage 1: interact 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzonitrile (stage 5, example 192) and 2-chlorobenzenesulfonamide procedure of example 1, step 7, obtaining the desired product with a yield of 77%.

Stage 2: the Nitrile from the previous stage converts tetrazol in accordance with the procedure of stage 7 of example 192, receiving specified in the header of the product with a yield of 45%. MS high resolution calc. for [C38H32Cl2N6O3S+N] 723,17065 found 723,1711.

Example 194 N-[2-(1-benzhydryl-5-chloro-3-{2-[4-(2H-tetrazol-5-yl)phenoxy]ethyl}-1H-indol-2-yl)ethyl]butane-1-sulfonamide

Stage 1: interact 4-{2-[2-(2-AMI is oethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzonitrile (stage 5, example 192) and 1-butanesulfinamide procedure of example 1, step 7, obtaining the desired product with a yield of 79%.

Stage 2: convert Nitrile in tetrazol in accordance with the procedure of stage 7 of example 192, receiving specified in the header of the product with a yield of 91%. MS high resolution calc. for [C36H37ClN6O3S+N] 669,24092 found 669,2409.

Example 195 N-[2-(1-benzhydryl-5-chloro-3-{2-[4-(2H-tetrazol-5-yl)phenoxy]ethyl}-1H-indol-2-yl)ethyl]-2,2,2-cryptgethashparam

Stage 1: interact 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzonitrile (stage 5, example 192) and 2,2,2-triftoruranmetilidina procedure of example 1, step 7, obtaining the desired product with a yield of 64%.

Stage 2: convert Nitrile in tetrazol in accordance with the procedure of stage 7 of example 192, receiving specified in the header of the product with a yield of 77%. MS high resolution calc. for [C34H30ClF3N6About3S+N] 695,18135 found 695,1807.

Example 196: 4-(2-{1-benzhydryl-5-chloro-2-[2-(2,4,6-tripersonality)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 2,4,6-tripersonality procedure of example 1, step 7 exit 92%.

Stage 2: Intermediate connection, not only the abuser an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 92%. MS high resolution calc. for [C38H30ClFN2O3S+N] 719,15889 found 719,15843.

Example 197: 4-(2-{1-benzhydryl-5-chloro-2-[2-(4-methoxy-2-nitrobenzenesulfonamide)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 4-methoxy-2-nitrobenzenesulfonamide procedure of example 1, step 7 to yield 74%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 94%. MS high resolution calc. for [C39H34ClN3O8S+N] 740,1828 found 740,1834.

Example 198: 4-(2-{1-benzhydryl-5-chloro-2-[2-(3-triftormetilfullerenov)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 3-(triptoreline)benzosulfimide procedure of example 1, step 7 exit 61%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header acid vyhoda is 86%. MS high resolution calc. for [C39H32ClF3N2O6S+N] 771,1514 found 771,1512.

Example 199: 4-(3-{1-benzhydryl-5-chloro-2-[2-(2,4,6-tripersonality)ethyl]-1H-indol-3-yl}propyl)benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add 2,4,6-tripersonality procedure of example 1, step 7, when receiving the product yield 61%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 97%. MS high resolution calc. for [C39H32ClF3N2O4S+N] 717,17962 found 741,17913.

Example 200: 4-(3-{1-benzhydryl-5-chloro-2-[2-(4-methoxy-2-nitrobenzenesulfonamide)ethyl]-1H-indol-3-yl}propyl)benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add 4-methoxy-2-nitrobenzenesulfonamide procedure of example 1, step 7, when receiving the product yield 81%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 95%. MS high resolution calc. for [C40H36ClN3O7S+N] 738,2035 found 738,2028.

When the EP 201: 4-(3-{1-benzhydryl-5-chloro-2-[2-(3-triftormetilfullerenov)ethyl]-1H-indol-3-yl}propyl)benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add 3-(triptoreline)benzosulphochloride procedure of example 1, step 7, when receiving the product yield 83%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 91%. MS high resolution calc. for [C40H34ClF3N2O5S+N] 747,19019 found 747,18996.

Example 202: 4-{2-[1-benzhydryl-5-chloro-2-{2-[({4-methylsulfonylbenzoyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add 4-methylsulfonylbenzoyl procedure of example 1, step 7, when receiving the product with the release of 65%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 100%. MS high resolution calc. for [C40H37ClN2O6S2+H] 741,18544 found 741,18421.

Example 203: 4-[2-{1-benzhydryl-5-chloro-2-[2-({[4-methylsulphonyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chlorine is-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 4-methylsulfonylbenzoyl procedure of example 1, step 7 exit 61%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 90%. MS high resolution calc. for [C39H35ClN2O7S2-N] 741,15014 found 741,14842.

Example 204: 4-{2-[1-benzhydryl-5-chloro-2-{2-[({2-methylsulfonylbenzoyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add 2-methylsulfonylbenzoyl procedure of example 1, step 7, when receiving the product with the release of 65%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 100%. MS high resolution calc. for [C40H37ClN2O6S2+H] 741,18544 found 741,18425.

Example 205: 4-(2-{1-benzhydryl-5-chloro 2-[2-({[2-methylsulphonyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 2-methylbenzenesulfonamide procedure of example 1, stage 7 with vyhoda is 61%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 90%. MS high resolution calc. for [C39H35ClH2O7S2+H] 743,16470 found 743,16431.

Example 206: 4-{2-[1-benzhydryl-5-chloro-2-{2-[({3-phenylsulfonyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add 3-vinylbenzenesulfonic procedure of example 1, step 7, when receiving the product with the release of 65%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 100%. MS high resolution calc. for [C45H39ClN2O4S+N] 739,23919 found 739,23896.

Example 207: 4-[2-(1-benzhydryl-2-{2-[(1,1'-biphenyl-3-ylsulphonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 3-vinylbenzenesulfonic procedure of example 1, step 7 exit 61%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 PR is a measure 1, receiving specified in the header of the acid with a yield of 90%. MS high resolution calc. for [C44H37ClN2O5S+N] 741,21845 found 741,21879.

Example 208: 4-{2-[1-benzhydryl-5-chloro-2-{2-[({2-triftormetilfullerenov}sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add 2-triftoratsetilatsetonom procedure of example 1, step 7, when receiving the product with the release of 65%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 100%. MS high resolution calc. for [C40H34F3ClN2O5S+N] 731,19527 found 731,19591.

Example 209: 4-[2-{1-benzhydryl-5-chloro-2-[2-({[2-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 2-triftormetilfullerenov procedure of example 1, step 7 exit 61%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 90%. MS high resolution calc. for[C 40H34F3ClN2O4S2+H] 733,17454 found 733,17439.

Example 210: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(5-methyl-1-phenyl-1H-Piramal-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add 5-methyl-1-phenyl-1L-pyrazole-4-sulphonylchloride procedure of example 1, step 7, when receiving the product with the release of 93%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 99%. MS high resolution calc. for [C43H39ClN4O4S+N] 743,24533 found 743,24506.

Example 211: 4-{2-[1-benzhydryl-5-chloro-2-{2-{[(5-methyl-1-phenyl-1H-pyrazole-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) is added 5-methyl-1-phenyl-1H-pyrazole-4-sulphonylchloride procedure of example 1, step 7, when receiving the product with the release of 88%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 100%. MS high resolution calc. for [C42H37ClN4O5S+N] 745,2246 found 745,22362.

Example 212: 4-{3-1-benzhydryl-5-chloro-2-(2-{[(1,3,5-trimethyl-1H-pyrazole-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add 1,3,5-trimethyl-1H-pyrazole-4-sulphonylchloride procedure of example 1, step 7, when receiving the product yield of 92%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 92%. MS high resolution calc. for [C39H39ClN4O4S+N] 695,24533 found 695,24453.

Example 213: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(1,3,5-trimethyl-1H-pyrazole-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) add 1,3,5-trimethyl-1H-pyrazole-4-sulphonylchloride procedure of example 1, step 7, getting the product out 100%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 74%. MS high resolution calc. for [C38H37ClN4About5S+N] 697,2246 found 697,2241.

Example 214: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,3-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) EXT the keys 2,3-dichlorobenzenesulfonyl procedure of example 1, stage 7, when receiving the product with the release of 85%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 96%. MS high resolution calc. for [C39H33Cl3N2O4S-N] 729,1154 found 729,1135.

Example 215: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,3-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) is added 2,3-dichlorobenzenesulfonyl procedure of example 1, step 7, when receiving the product yield 79%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 97%. MS high resolution calc. for [C38H31Cl3N2O5S-N] 731,0947 found 731,0930.

Example 216: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(4'-fluoro-1,1'-diphenyl-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add 4'-forfinal-4-benzosulphochloride procedure of example 1, step 7, when receiving the product with the release of 65%.

Stage 2: Intermediate connection, a complex EF the R, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 100%. MS high resolution calc. for [C45H38ClFN2O4S+N] 757,22976 found 757,22874.

Example 217: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(4'-fluoro-1,1'-diphenyl-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 4'-forfinal-4-benzosulfimide procedure of example 1, step 7 exit 61%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 90%. MS high resolution calc. for [C44H36ClFN2O5S+N] 759,20903 found 759,20745.

Example 218: 4-{2-[1-benzhydryl-5-chloro-2-{2-[({3-cryptomaterial}sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add 3-triftoratsetilatsetonom procedure of example 1, step 7, when receiving the product with the release of 65%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 100%. MS is high resolution calc. for [C40H37ClF3N2O4S+N] 731,19527 found 731,19582.

Example 219: 4-(2-{1-benzhydryl-5-chloro 2-[2-({[3-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 3-triftormetilfullerenov procedure of example 1, step 7 exit 61%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 90%. MS high resolution calc. for [C39H35ClF3N2O5S+N] 733,17454 found 733,17431.

Example 220: 4-[2-(1-benzhydryl-5-chloro-2-{2-[({[(3,4-dichlorophenyl)thio]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: To the methyl 4-{2-[1-benzhydryl-5-chloro-2-(2-chloromethanesulfonyl)-1H-indol-3-yl]ethoxy}benzoate, example 81, step 1, add 3,4-dichlorothiophene procedure of example 81, step 2. The crude substance is purified preparative HPLC to yield of ester 24% and acid 14%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 97%. m/z (M-1) 779,01.

Example 221: 4-[2-(1-benzhydryl-5-chloro-2-{2-[({[(3-CHL is R-4-forfinal)thio]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: To the methyl 4-{2-[1-benzhydryl-5-chloro-2-(2-chloromethanesulfonyl)-1H-indol-3-yl]ethoxy}benzoate, example 81, step 1, add 3-chloro-4-portifino procedure of example 81, step 2. The product was then purified column flash chromatography using a mixture of 30% EtOAc/hexane with the release of 70%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 89%. m/z (M-1) 760,94.

Example 222: 4-[2-(1-benzhydryl-5-chloro-2-{2-[({2-torbenson}sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add 2-forbindelsesfaneblad procedure of example 1, step 7, when receiving the product with the release of 65%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 100%. MS high resolution calc. for [C39H34ClFN2O4S+N] 681,19846 found 699,19854.

Example 223: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-forfinal)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 2-forbindelse is theilhard procedure of example 1, stage 7 with the release of 61%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 90%. MS high resolution calc. for [C38H33ClFN2O5S+N] 683,17773 found 683,17694.

Example 224: 4-[2-(1-benzhydryl-5-chloro-2-{2-[({2,6-differenza}sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) is added 2,6-differentialalgebraic procedure of example 1, step 7, when receiving the product with the release of 65%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 100%. MS high resolution calc. for [C39H33ClF2N2O4S+N] 699,18904 found 699,18850.

Example 225: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-differenl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 2,6-differentialthreshold procedure of example 1, step 7 exit 61%.

Stage 2: Intermediate connection representing an ester, hydrolyzing the CE is provided with the stage 8 of example 1, receiving specified in the header of the acid with a yield of 90%. MS high resolution calc. for [C38H32ClF2N2O5S+N] 701,16831 found 701,16849.

Example 226: 4-[2-(1-benzhydryl-5-chloro-2-{2-[({2-chloro-6-methylbenzoyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) is added 2-chloro-6-methylbenzenesulfonamide procedure of example 1, step 7, when receiving the product with the release of 65%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 100%. MS high resolution calc. for [C40H36Cl2O4S+N] 711,18456 found 711,18404.

Example 227: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-chloro-6-were)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 2-chloro-6-methylbenzenesulfonamide procedure of example 1, step 7 exit 61%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 90%. MS high resolution calc. for [C39H34C 2N2O5S+N] 713,16383 found 713,16269.

Example 228: 4-[2-(1-benzhydryl-5-chloro-2-{2-[({4-cryptomaterial}sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add 4-triftoratsetilatsetonom procedure of example 1, step 7, when receiving the product with the release of 65%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 100%. MS high resolution calc. for [C40H37ClF3N2O4S+N] 731,19527 found 731,19580.

Example 229: 4-(2-{1-benzhydryl-5-chloro-2-[2-({[(4-trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 4-triftormetilfullerenov procedure of example 1, step 7 exit 61%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 90%. MS high resolution calc. for [C39H35ClF3N2O5S+N] 733,17454 found 733,17432.

Example 230: 4-[2-(1-benzhydryl-5-chloro-2-{2-[({2-Tr is pharmacokinet}sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add 2-triftormetilfullerenov procedure of example 1, step 7, when receiving the product with the release of 65%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 100%. MS high resolution calc. for [C40H37ClF3N2O5S+N] 747,19019 found 747,18848.

Example 231: 4-(2-{5-chloro-1-(diphenylmethyl)-2-[2-({[(2-triptoreline)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 2-triftormetilfullerenov procedure of example 1, step 7 exit 61%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 90%. MS high resolution calc. for [C39H35ClF3N2O6S+N] 749,16945 found 733,16813.

Example 232: 4-[2-(1-benzhydryl-5-chloro-2-{2-[({2-methylbenzoyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (article is Diya 6, example 42) add 2-methylbenzenesulfonamide procedure of example 1, step 7, when receiving the product with the release of 65%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 100%. MS high resolution calc. for [C40H37ClN2O4S+N] 677,22354 found 677,22244.

Example 233: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-were)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 2-methylbenzenesulfonamide procedure of example 1, step 7 exit 61%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 90%. MS high resolution calc. for [C39H35ClN2O5S+N] 679,20280 found 679,20197.

Example 234: 4-[2-(1-benzhydryl-5-chloro-2-{2-[({2-methoxybenzoyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add 2-methoxybenzenesulfonamide procedure of example 1, step 7, when receiving the product with the release of 65%.

Stage 2: the Ex is offered by the connection, representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 100%. MS high resolution calc. for [C40H37ClN2O5S+N] 693,2185 found 693,21852.

Example 235: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-methoxyphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 2-methoxybenzenesulfonamide procedure of example 1, step 7 exit 61%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 90%. MS high resolution calc. for [C39H35ClN2O6S+N] 695,19722 found 695,19701.

Example 236: 4-[2-(1-benzhydryl-5-chloro-2-{2-[({2-tert-butylbenzoyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) is added 2-tert-butylbenzenesulfonamide procedure of example 1, step 7, when receiving the product with the release of 65%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header sour is at exit 100%. MS high resolution calc. for [C43H43ClN2O4S+N] 719,27049 found 719,27057.

Example 237: 4-{2-[1-benzhydryl-2-(2-{[(2-tert-butylphenyl)sulfonyl]amino}ethyl)-5-chloro-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 2-tert-butylbenzenesulfonamide procedure of example 1, step 7 exit 61%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 90%. MS high resolution calc. for [C42H41ClN2O5S+N] 721,24975 found 721,24907.

Example 238: 4-[2-(1-benzhydryl-5-chloro-2-{2-[({2-methyldibenzo}sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add 2-methyldibenzothiophene procedure of example 1, step 7, when receiving the product with the release of 65%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 100%. MS high resolution calc. for [C40H37ClN2O4S2+H] 709,19561 found 709,19504.

Example 239: 4-(2-{1-who enshell-5-chloro-2-[2-({[2-(methylthio)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 2-methyldibenzothiophene procedure of example 1, step 7 exit 61%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 90%. MS high resolution calc. for [C39H35ClN2O5S2+H] 711,17487 found 711,17518.

Example 240: 4-[2-(1-benzhydryl-5-chloro-2-{2-[({3-chloro-2-methylbenzoyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) is added 3-chloro-2-methylbenzenesulfonamide procedure of example 1, step 7, when receiving the product with the release of 65%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 100%. MS high resolution calc. for [C40H36Cl2N2O4S+N] 711,18456 found 711,18465.

Example 241: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3-chloro-2-were)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]atok and}benzoate (step 6, example 1) and 3-chloro-2-methylbenzenesulfonamide procedure of example 1, step 7 exit 61%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 90%. MS high resolution calc. for [C39H34Cl2N2O5S2+H] 713,16383 found 713,16296.

Example 242: 4-[2-(2-{2-[2-(4-acetylpiperidine-1-yl)ethanolgasoline]ethyl}-1-benzhydryl-5-chloro-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1; get Connection with the release of 91% of the intermediate compound of example 87, step 1 and 1-acetylpiperidine procedure of example 87, step 2, except that the mixture is heated at 60°C for 19 h.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 19%. m/z (M-1) 741,2.

Example 243: 4-[2-(1-benzhydryl-5-chloro-2-{2-[2-(3,5-dimethylpiperazine-1-yl)ethanolgasoline]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: Connection to get out 97% of the intermediate compound of example 87, step 1 and CIS-2,6-dimethylpiperazine procedure of example 87, step 2, except that the mixture is heated at 60°C for 19 h.

Stage 2: Intermediate connection, representing the false ether, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 39%. m/z (M-1) 727,2.

Example 244: 4-[2-(2-{2-[2-(4-acetyl-Z,5-dimethylpiperazine-1-yl)ethanolgasoline]ethyl}-1-benzhydryl-5-chloro-1H-indol-3-yl)ethoxy]benzoic acid

Step 1: To a solution of methyl ester 4-[2-(1-benzhydryl-5-chloro-2-{2-[2-(3,5-dimethylpiperazine-1-yl)ethanolgasoline]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid (stage 1, the previous example) (31 mg, 0,042 mmol) in CH2Cl2(1 ml) at 0°add Et3N (0.10 ml) and AU2O (60 ml) and the reaction mixture was stirred at room temperature for 4 hours. Water treatment, followed by chromatography on silica gel (3.5% of the Meon/Meon), gives the desired intermediate compound, which represents an ester (17 mg, yield 52%).

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 96%. m/z (M-1) 771,2.

Example 245: 4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(4-methylpiperidin-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: the Compound is prepared from intermediate compound of example 87, step 1 and 1-acetylpiperidine 4-methylpiperidine procedure of example 87, step 2. The product was then purified column flash chromatography using a mixture 50-0% EtOAc/hexane to yield 87%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, except that regulate pH to 4-5, receiving specified in the header of the acid with a yield of 91%. m/z (M-1) 712,3.

Example 246: 4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(3-methylpiperidin-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: the Compound is prepared from intermediate compound of example 87, step 1 and 3-methylpiperidine procedure of example 87, step 2. The product was then purified column flash chromatography using a mixture of 50-60% EtOAc/hexane to yield 94%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, except that regulate pH to 4-5, receiving specified in the header of the acid with a yield of 87%. MS high resolution calc. for [C40H44ClN3O5S+N] 714,2763 found 714,2765.

Example 247: 4-[2-(1-benzhydryl-2-{2-[2-(2-carbamoylation-1-yl)ethanolgasoline]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: the Compound is prepared from intermediate compound of example 87, step 1 and L-prolinamide procedure of example 87, step 2. The product was then purified column flash chromatography using EtOAc to yield 86%.

Stage 2: Intermediate connection, a complex EPE is, hydrolyzing in accordance with the stage 8 of example 1, except that regulate pH to 4-5, receiving specified in the header of the acid with a yield of 43% after preparative HPLC. MS high resolution calc. for [C39H41ClN4O6S+N] 729,2508 found 729,251.

Example 248: 4-[2-(1-benzhydryl-5-chloro-2-{2-[({2-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]ethyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: Connection obtained from the intermediate of example 87, step 1 and (S)-(+)-2-(methoxymethyl)pyrrolidine procedure of example 87, step 2. The product was then purified column flash chromatography using a mixture of 80% EtOAc/hexane to yield 87%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1 except that regulate pH to 4-5, receiving specified in the header of the acid with a yield of 87%. MS high resolution calc. for [C40H44ClN3O6S+N] 730,2712 found 730,2709.

Example 249: 4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(2-ethylpiperidine-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: Connection obtained from the intermediate of example 87, step 1 and 2-ethylpiperidine procedure of example 87, step 2. The product was then purified column flash chromatography using a mixture of 50-60% EtOAc/hexane with vyhoda is 73%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1 except that regulate pH to 4-5, receiving specified in the header of the acid with a yield of 38% after purification preparative HPLC. MS high resolution calc. for [C41H-46ClN3O5S+N] 728,292 found 728,2925.

Example 250: 4-[2-(1-benzhydryl-5-chloro-2-{2-[({2-[(3R,5S) - for 3,5-dimethylmorpholine-4-yl]ethyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: Connection obtained from the intermediate of example 87, step 1 and CIS-2,6-dimethylmorpholine procedure of example 87, step 2. The product was then purified column flash chromatography using a mixture of 50% EtOAc/hexane to yield 79%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, except that regulate pH to 4-5, receiving specified in the header of the acid with a yield of 94%. m/z (M-1) 729,4.

Example 251: 4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: Connection obtained from the intermediate of example 87, step 1 and (1S,4S)-(+)-2-Aza-5-oxabicyclo-[2.2.1]-heptane hydrochloride by the procedure of example 87, step 2. The product was then purified on CombiFlash mixture 1-7% MeOH/CH2Cl2with the release of 85%.

With the adiya 2: Intermediate connection, representing an ester, hydrolyzing in accordance with the stage 8 of example 1 except that regulate pH to 4-5, receiving specified in the header of the acid with a yield of 100%. MS high resolution calc. for [C39H40ClN3About6S+N] 714,2399 found 714,2397.

Example 252: 4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(2-isopropylpyrimidine-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: Connection obtained from the intermediate of example 87, step 1 and 2-(methylethyl)pyrrolidine hydrochloride by the procedure of example 87, step 2. The product was then purified by CombiFlash with a mixture of 1-5% MeOH/CH2Cl2with the release of 61%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1 except that regulate pH to 4-5, receiving specified in the header of the acid with a yield of 97%. MS high resolution calc. for [C41H46ClN3O5S+N] 728,292 found 728,293.

Example 253: 4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(2-methyl-3-oxopiperidin-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: Connection obtained from the intermediate of example 87, step 1 and 3-methyl-2-piperazinone procedure of example 87, step 2. The product was then purified column flash chromatography using a mixture of 5% MeOH/CH2Cl2with vyhoda%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, except that regulate pH to 4-5, receiving specified in the header of the acid with a yield of 29% after purification preparative HPLC. MS high resolution calc. for [C39H41ClN4O6S+N] 729,2508 found 729,2501.

Example 254: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add 2-chlorobenzenesulfonamide procedure of example 1, step 7, when receiving the product yield 66%.1H NMR (400 MHz, CDCI3) δ ppm of 1.94 (m, 2H), 2,74 (m, 6N), of 2.97 (m, 2H), 3,91 (s, 3H), 4,94 (t, J=6,32 Hz, 1H), 6.48 in (d, J=a 9.09 Hz, 1H), 6,79 (DD, J=8,84, 2,02 Hz, 1H), 6,83 (C, 1 ad), 7,03 (m, 4H), 7,26 (m, N), 7,39 (d, J=2,02 Hz, 1H), 7,44 (d, J=3,54 Hz, 2H), of 7.90 (d, J=7,58 Hz, 1H), of 7.96 (d, J=8.34 per Hz, 2H).

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining, after flash chromatography indicated in the header of the acid with a yield of 84%.1H NMR (400 MHz, CDCl3) δ ppm to 1.96 (m, 2H), was 2.76 (m, 6N), 2,98 (m, 2H), 5,00 (t, J=6,32 Hz, 1H), 6,79 (DD, J=8,84, 2,02 Hz, 1H), 6,84 (s, 1H),? 7.04 baby mortality (m, 4H), 7,28 (m, 10H), 7,40 (d, J=l,77 Hz, 1H), 7,45 (d, J=3,79 Hz, 2H), of 7.90 (d, J=7,58 Hz, 1H), 8,02 (d, J=8.34 per Hz, 2H). MS high resolution calc. for [C39H4 Cl2N2O4S·Na] 719,1514 found (ERIE) 695,15363.

Example 255: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate and 2-chlorobenzenesulfonamide procedure of example 1, stage 7 with the release of 86%.1H NMR (400 MHz, DMSO-D6) δ at 2.93 ppm (m, 2H), to 3.02 (m, 2H), 3,11 (t, J=6,57 Hz, 2H), 3,81 (s, 3H), 4,19 (t, J=6,57 Hz, 2H), of 6.49 (d, J=8,84 Hz, 1H), 6,80 (DD, J=8,84, 2,02 Hz, 1H), of 6.96 (d, J=8,84 Hz, 2H), 7,01 (s, 1H),? 7.04 baby mortality (DD, J=6,95, 2,40 Hz, 4H), 7,34 (m, 5H), 7,40 (m, 1H), 7,60 (m, 3H), 7,80 (DD, J=7,83, of 1.52 Hz, 1H), 7,86 (d, J=8,84 Hz, 2H), 8,11 (t, J=of 5.81 Hz, 1H).

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1. The crude substance is purified flash chromatography, receiving specified in the header of the acid with a yield of 74%.1H NMR (400 MHz, CDCl3) δ ppm 2,89 (m, 2H), 3,18 (t, J=6,57 Hz, 2H), 4,20 (t, J=6,57 Hz, 2H), 5,09 (t, J=6,32 Hz, 1H), 6,53 (d, J=8,84 Hz, 1H), PC 6.82 (m, 3H), 6.90 to (s, 1H), 7,05 (m, 4H), 7,26 (m, 7H), was 7.45 (m, 2H), 7,52 (d, J=2,02 Hz, 1H), of 7.90 (m, 1H), 8,00 (d, J=8,84 Hz, 2H). MS high resolution calc. for C38H32Cl2N2O5S 698,1409 found (ERI+) 699,14786. Elem. analysis calc. for C38H32Cl2N2O5S: 65,23; N Br4.61; 4,00 N; found: 65,02; N. Of 4.44; N 3,94.

Example 256: 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorophenyl)sulfonyl]Amin is}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoic acid

Stage 1: This compound is obtained from the methyl ester of 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]econsultancy}benzoic acid and 2-chlorobenzenesulfonamide procedure of example 1, stage 7 with the release of 48%.1HNMR (400 MHz, CDCl3) δ ppm 2,88 (sq, J=7,07 Hz, 2H), 3,03 (t, J=7,33 Hz, 2H), 3,20 (m, 2H), 3.43 points (m, 2H), of 3.97 (s, 3H), 5,18 (t, J=6,44 Hz, 1H), 6,46 (d, J=8,84 Hz, 1H), 6,78 (DD, J=8,97, of 2.15 Hz, 1h), 6,84 (s, 1H),? 7.04 baby mortality (DD, J=6,69, 2,40 Hz, 4H), 7,21 (d, J=2,02 Hz, 1H), 7,31 (m, 7H), of 7.48 (d, J=3,79 Hz, 2H), to $ 7.91 (d, J=7,58 Hz, 1H), 8,08 (d, J=8,59 Hz, 2H), 8,24 (m, 2H).

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 97%.1H NMR (400 MHz, CDCl3) δ ppm 2,88 (sq, J=6,91 Hz, 2H), 3.04 from (t, J=7,20 Hz, 2H), up 3.22 (m, 2H), of 3.45 (m, 2H), 5.25 in (t, J=6,44 Hz, 1H), 6,47 (d, J=a 9.09 Hz, 1 H.), of 6.78 (DD, J=8,84, 2,02 Hz, 1 BC), at 6.84 (s, 1H),? 7.04 baby mortality (DD, J=6,57, 2,53 Hz, 4H), 7,22 (d, J=2,02 Hz, 1H), 7,31 (m, 7H), of 7.48 (d, J=3,79 Hz, 2H), 7,92 (d, J=7,83 Hz, 1H), 8,12 (d, J=8,59 Hz, 2H), 8,28 (d, J=8.34 per Hz, 2H).

Example 257: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate added 1,2-dimethylimidazole-4-sulphonylchloride procedure of example 1, step 7, when receiving the product with yields of 80%.1H NMR (400 MHz, DMSO-D6) δ to 1.86 ppm (m, 2H), 2,18 (s, 3H), 2,71 (m, 4H), to 2.94 (m, 4H), 3,49 (C, H), a 3.83 (s, 3H), 6.42 per (d, J=8,84 Hz, 1H), 6,76 (DD, J=8,84, 2,02 Hz, 1H), 7,06 (m, 4H), of 7.36 (m, 8H), 7,44 (d, J=2,02 Hz, 1H), 7,49 (s, 1H), to 7.59 (s, 1H), 7,87 (d, J=8,08 Hz, 2H).

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 61%.1H NMR (400 MHz, DMSO-D6) δ of 1.87 ppm (m, 2H), 2,18 (s, 3H), 2,70 (t, J=7,58 Hz, 4H), 2.95 and (m, 4H), 3,49 (s, 3H), 6.42 per (d, J=8,84 Hz, 1H), 6,76 (DD, J=8,84, 2,02 Hz, 1H), 7,06 (m, 5H), 7,35 (m, 8H), 7,44 (d, J=2,02 Hz, 1H), 7,49 (s, 1H), to 7.59 (t, J=4,93 Hz, 1H), a 7.85 (d, J=8.34 per Hz, 2H). MS high resolution Calc. for C38H37ClN4O4S 680,2224 found (ERI+) 681, 22879.

Example 258: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: This compound is prepared from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate and 1,2-dimethylimidazole-4-sulphonylchloride procedure of example 1, stage 7 with the release of 84%.1H NMR (400 MHz, CDCl3) δ to 2.25 ppm (s, 3H), of 3.07 (m, 2H), 3,13 (m, 2H), 3,18 (t, J=6,82 Hz, 2H), 3,39 (s, 3H), 3,88 (s, 3H), 4,17 (t, J=6.69 in Hz, 2H), and 5.30 (m, J=2,78 Hz, 1H), 6,47 (d, J=a 9.09 Hz, 1H), 6,79 (DD, J=8,84, 2,02 Hz, 1H), 6,83 (d, J=8,84 Hz, 2H), 6,93 (s, 1H), was 7.08 (m, 5H), 7,29 (m, 6N), 7,51 (d, J=2,02 Hz, 1H), 7,94 (d, J=8,84 Hz, 2H).

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header acid vyhoda is 55%. 1H NMR (400 MHz, DMSO-D6) δ ppm 2,17 (s, 3H), to 3.02 (m, J=9,10 Hz, 4H), 3,14 (t, J=6,57 Hz, 2H), 3,47 (s, 3H), is 4.21 (t, J=6.69 in Hz, 2H), 6,47 (d, J=8,84 Hz, 1H), 6,79 (DD, J=8,84, and 2.27 Hz, 1H), of 6.96 (d, J=8,84 Hz, 2H), 7,07 (m, 5H)that was 7.36 (m, 6N), 7,49 (s, 1H), 7,63 (m, 2H), to 7.84 (d, J=8,84 Hz, 2H). MS high resolution calc. for C37H35ClN4O5S 682,2017 found (ERI+) 683,20812.

Example 259: 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propionic acid

Stage 1. This compound is obtained from the ethyl ester of 3-(4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]econsultancy}phenyl)propionic acid and 2-chlorobenzenesulfonamide procedure of example 1, step 7 exit 78%.1H NMR (400 MHz, CDCl3) δ of 1.25 ppm (m, 3H), of 2.66 (t, J=7,58 Hz, 2H), 2,88 (sq, J=6.48 in Hz, 2H), of 3.07 (m, 6N), to 3.34 (m, 2H), 4,12 (sq, J=7,07 Hz, 2H), 5,31 (t, J=6,32 Hz, 1H), 6,45 (d, J=8,84 Hz, 1H), 6,77 (DD, J=8,84, 2,02 Hz, 1H), 6,85 (s, 1H),? 7.04 baby mortality (m, 4H), 7,16 (d, J=l,77 Hz, 1H), 7,30 (m, 7H), 7,46 (m, 4H), to $ 7.91 (m, 3H).

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, after receiving flash chromatography indicated in the header of the acid with a yield of 41%.1H NMR (400 MHz, CDCl3) δ to 2.74 ppm (s, 4H), of 2.86 (t, J=6.69 in Hz, 2H), 2,93 (m, 2H), is 3.08 (t, J=6,57 Hz, 2H), 3,29 (m, 2H), to 6.43 (d, J=8,84 Hz, 1H), is 6.61 (s, 1H), 6,78 (m, 2H), 7,00 (m, 4H), 7,25 (m, 7H), was 7.36 (d, J=l,77 Hz, 1H), 7,45 (m, 2H), 7,50 (d, J=8.34 per Hz, 2H), 7,80 (d, J=7,58 Hz, 1H), to 7.93 (d, J=8.34 per Hz, 2H). MS high level of the resolution calc. for C40H36Cl2N2O6S2(M-N) 773,1319 found 773,13107.

Example 260: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3-chloro-4-were)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: This compound is prepared from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1L-indol-3-yl]ethoxy}benzoate and 3-chloro-4-methylbenzenesulfonamide procedure of example 1, stage 7 with the release of 100%.1H NMR (400 MHz, CDCl3) δ of 2.38 ppm (s, 3H), 2,92 (sq, J=6,99 Hz, 2H), to 3.09 (t, J=7,58 Hz, 2H), 3,18 (t, J=6,44 Hz, 2H), 3,88 (s, 3H), is 4.21 (t, J=6,44 Hz, 2H), 4,42 (t, J=6,44 Hz, 1H), is 6.54 (d, J=8,84 Hz, 1H), 6,79 (m, 2H), 6,83 (DD, J=8,84, 2,02 Hz, 1H), to 6.88 (s, 1H),? 7.04 baby mortality (m, 4H), 7,20 (d, J=8,08 Hz, 1H), 7,29 (m, 6N), 7,40 (DD, J=of 7.96, 1.89 Hz, 1H), 7,52 (d, J=2,02 Hz, 1H), 7,66 (d, J=1.77 Hz, 1H), to 7.93 (m, 2H).

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1. The crude product is purified flash chromatography, receiving specified in the header of the acid with a yield of 69%.1H NMR (400 MHz, CDCl3) δ of 2.38 ppm (s, 3H), of 2.93 (m, 2H), 3,10 (t, J=7,45 Hz, 2H), 3,19 (t, J=6,44 Hz, 2H), 4,23 (t, J=6,44 Hz, 2H), to 4.52 (s, 1H), is 6.54 (d, J=8,84 Hz, 1H), 6,83 (m, 3H), 6.89 in (s, 1H),? 7.04 baby mortality (m, 4H), 7,20 (d, J=8,08 Hz, 1H), 7,29 (m, 6N), 7,40 (DD, J=8,08, 1.77 Hz, 1H), 7,53 (d, J=2,02 Hz, 1H), to 7.67 (d, J=2,02 Hz, 1H), 7,98 (d, J=8,84 Hz, 2H). MS high resolution calc. for C39H34Cl2N2O5S 712,1565 found (ERI+) 713,16268. E. anal. calc. for C39H34Cl2N2O5S: what, 65,64; N, 4,80; N, 3,93. Found: C, 65,62; N, To 4.52; N, Of 3.73.

Example 261: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-chloro-4-were)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate added 3-chloro-4-methylbenzenesulfonamide procedure of example 1, step 7, when receiving the product with the release of 98%.1H NMR (400 MHz, CDCl3) δ ppm of 1.95 (m, 2H), 2.40 a (s, 3H), 2,72 (sq, J=8,25 Hz, 4H), 2,82 (sq, J=6,74 Hz, 2H), 2,96 (t, J=7,33 Hz, 2H), 3,91 (s, 3H), 4,27 (t, J=6,44 Hz, 1H), of 6.49 (d, J=8,84 Hz, 1H), 6,80 (DD, J=8,97, of 2.15 Hz, 1H), PC 6.82 (s, 1H), 7,02 (m, 4H), 7,26 (m, N), 7,38 (DD, J=of 7.96, 1.89 Hz, 1H), 7,40 (d, J=2,02 Hz, 1H), 7,66 (d, J=l,77 Hz, 1H), of 7.96 (d, J=8.34 per Hz, 2H).

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, after receiving flash chromatography indicated in the header of the acid with a yield of 40%.1H NMR (400 MHz, CDCl3) δ ppm to 1.96 (m, 2H), 2.40 a (s, 3H), by 2.73 (m, 4H), and 2.83 (m, 2H), 2,98 (t, J=7,33 Hz, 2H), 4,33 (t, J=6,32 Hz, 1H), of 6.49 (d, J=8,84 Hz, 1H), 6,80 (DD, J=8,84, and 2.27 Hz, 1H), 6,83 (s, 1H), 7,02 (m, 4H), 7,21 (d, J=7,83 Hz, 1H), 7,29 (m, 8H), 7,39 (m, 2H), 7,66 (d, J=l,77 Hz, 1H), 8,00 (d, J=8,08 Hz, 2H). MS high resolution calc. for C40H36Cl2N2O4S 710,1773 found (ERI+) 711,18411. E. anal. calc. for C40H36Cl2N2O4S: C, 67,51; N, 5,10; N, 3,94. Found: C, 67,67; N, At 5.27; N, 3,81.

Example 262: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3-chloro-5-fluoro-2-were)sulfo the yl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: This compound is prepared from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate and 3-chloro-5-fluoro-2-methylbenzenesulfonamide procedure of example 1, stage 7 with the release of 100%.1H NMR (400 MHz, CDCl3) δ and 2.26 ppm (s, 3H), 2,99 (m, 2H), 3,10 (m, 2H), 3,18 (t, J=6,57 Hz, 2H), 3,88 (s, 3H), is 4.21 (t, J=6,57 Hz, 2H), 4,71 (t, J=6,32 Hz, 1H), of 6.52 (d, J=8,84 Hz, 1H), for 6.81 (m, 3H), to 6.88 (s, 1H),? 7.04 baby mortality (m, 4H), 7,14 (d, J=a 9.60 Hz, 1H), 7,29 (m, 6N), 7,52 (d, J=2,02 Hz, 1H), 7,58 (d, J=7,58 Hz, 1H), 7,94 (m, 2H).

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 69%.1H NMR (400 MHz, CDCl3) δ and 2.26 ppm (s, 3H), 2,99 (m, 2H), 3,11 (m, 2H), 3,19 (t, J=6,44 Hz, 2H), 4,23 (t, J=6,44 Hz, 2H), 4,79 (t, J=6,32 Hz, 1H), of 6.52 (d, J=8,84 Hz, 1H), 6,83 (m, 3H), to 6.88 (s, 1H),? 7.04 baby mortality (m, 4H), to 7.15 (d, J=a 9.60 Hz, 1H), 7,29 (m, 6N), 7,52 (d, J=2,02 Hz, 1H), to 7.59 (d, J=7,58 Hz, 1H), to 7.99 (d, J=8,84 Hz, 2H). MS high resolution calc. for C39H33Cl2FN2O5S 730,1471 found (ERI+) 731,1532.

Example 263: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-chloro-5-fluoro-2-were)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate added 3-chloro-5-fluoro-2-methylbenzenesulfonamide procedure of example 1, step 7, when receiving the product with a yield of 75%.1H NMR (400 MHz, CDCl3) δ ppm of 1.95 (m, 2H), and 2.27 (s, 3H), 2,72 (sq J=7,58 Hz, 4H), 2,89 (t, J=6,82 Hz, 2H), 2,97 (m, 2H), 3,91 (s, 3H), 4,59 (t, J=to 6.19 Hz, 1H), 6,47 (d, J=8,84 Hz, 1H), 6,80 (DD, J=8,97, of 2.15 Hz, 1H), PC 6.82 (s, 1H), 7,03 (DD, J=6,82, 2,53 Hz, 4H), 7,13 (d, J=9, 60 Hz, 1H), from 7.24 (d, J=8.34 per Hz, 2H), 7,29 (m, 6N), 7,40 (d, J=2,02 Hz, 1H) 7,58 (d, J=7,58 Hz, 1H), of 7.96 (d, J=8.34 per Hz, 2H).

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 96%.1H NMR (400 MHz, CDCl3) δ ppm to 1.96 (m, 2H), 2,28 (s, 3H), 2,74 (m, 4H), 2,89 (m, 2H), 2,99 (m, 2H)and 4.65 (sq, J=6,32 Hz, 1H), 6,47 (d, J=8,84 Hz, 1H), 6,80 (DD, J=8,97, of 2.15 Hz, 1H), PC 6.82 (s, 1H), 7,03 (m, 4H), 7,14 (d, J=9,60 Hz, 1H), 7,30 (m, 8H), 7,40 (d, J=2,02 Hz, 1H), 7,58 (d, J=7,58 Hz, 1H), 8,01 (d, J=8,08 Hz, 2H). MS high resolution calc. for C40H35Cl2FN2O4S 728,1679 found (ERI+) 729,17441. E. anal. calc. for C40H35Cl2FN2O4S: C, 65,84; N, A 4.83; N, 3,84. Found: C, 65,49; N, 5,02; N, 3.72 Points.

Example 264: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-nitrophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add 2-nitrobenzenesulfonamide procedure of example 1, step 7, when receiving the product yield 74%.1H NMR (400 MHz, CDCl3) δ ppm of 1.97 (m, 2H), 2,73 (sq, J=8,08 Hz, 4H), 2.91 in (m, 2H), 3.04 from (m, 2H), 3,91 (s, 3H), 5,33 (t, J=6,06 Hz, 1H), of 6.52 (d, J=8,84 Hz, 1H), 6,80 (DD, J=8,84, 2,02 Hz, 1H), 6.90 to (s, 1H), 7,06 (DD, J=6,57, 2,53 Hz, 4H), from 7.24 (d, J=8.34 per Hz, 2H),7,29 (m, 6N), 7,39 (d, J=2,02 Hz, 1H), 7,50 (TD, J=7,71, of 1.26 Hz, 1H), 7,65 (TD, J=to 7.77, 1.39 Hz, 1H), of 7.75 (DD, J=7,83, of 1.26 Hz, 1H), 7,80 (DD, J=of 7.96, to 1.14 Hz, 1H), of 7.96 (d, J=8,08 Hz, 2H).

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 100%.1H NMR (400 MHz, CDCl3) δ to 1.98 ppm (m, 2H), 2,75 (m, 4H), of 2.92 (m, 2H), 3,06 (m, 2H), 5,35 (t, J=6,06 Hz, 1H), of 6.52 (d, J=8,84 Hz, 1H), for 6.81 (DD, J=8,84, 2,02 Hz, 1H), 6,91 (s, 1H), 7,07 (DD, J=6,82, 2,53 Hz, 4H), 7,29 (m, 8H), 7,40 (d, J=2,02 Hz, 1H), 7,51 (m, 1H), 7,66 (m, 1H), 7,76 (DD, J=7,83, of 1.26 Hz, 1H), 7,81 (DD, J=of 7.96, to 1.14 Hz, 1H), 8,01 (d, J=8.34 per Hz, 2H). MC high resolution calc. for C39H34ClN3O6S 707,18568 found (ERI+) 708,19296.

Example 265: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-nitrophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: This compound is prepared from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate and 2-nitrosomethylurea procedure of example 1, step 7 exit 63%.1H NMR (400 MHz, CDCl3) δ ppm to 2.99 (m, 2H), 3,19 (m, 4H), 3,88 (s, 3H), is 4.21 (t, J=6,57 Hz, 2H), of 5.40 (t, J=to 6.19 Hz, 1H), to 6.57 (d, J=8,84 Hz, 1H), PC 6.82 (m, 3H), of 6.96 (s, 1H), was 7.08 (m, 4H), 7,29 (m, 6N), 7,49 (TD, J=7,71, 1,26 Hz, 1H), 7,52 (d, J=l,77 Hz, 1H), 7,65 (TD, J=7,71, of 1.26 Hz, 1H), 7,80 (m, 2H), to 7.93 (d, 2H).

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with which hodom 90%. 1H NMR (400 MHz, CDCl3) δ ppm to 2.99 (m, 2H), 3,20 (m, 4H), to 4.23 (t, J=6,57 Hz, 2H), of 5.40 (t, J=to 6.19 Hz, 1H), to 6.57 (d, J=8,84 Hz, 1H), 6,84 (m, 3H), 6,95 (s, 1H), was 7.08 (m, J=5,68, 3,66 Hz, 4H), 7,29 (m, 6N), to 7.50 (m, 2H), 7,65 (TD, J=to 7.77, 1.39 Hz, 1H), 7,80 (m, 2H), 7,98 (d, 2H). MS high resolution calc. for C38H32ClN3O7S 709,16495 found (ERI+) 710,17059.

Example 266: 4-[2-(1-benzhydryl-5-chloro-2-{2-[(mesitylenesulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate and 2-mesitylenesulfonyl procedure of example 1, step 7 exit 89%.1H NMR (400 MHz, CDCl3) δ ppm 2,24 (s, 3H), 2,48 (C, 6N), 2,90 (m, 2H), 3,05 (m, 2H), and 3.16 (t, J=6.69 in Hz, 2H), with 3.89 (s, 3H), 4,17 (t, J=6.69 in Hz, 2H), 4,48 (t, J=6,44 Hz, 1H), of 6.52 (d, J=8,84 Hz, 1H).

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 68%.1H NMR (400 MHz, CDCl3) δ ppm 2,24 (s, 3H), 2,48 (C, 6N), 2,90 (sq, J=6,99 Hz, 2H), 3,06 (m, 2H), 3,17 (t, J=6.69 in Hz, 2H), 4,19 (t, J=6,57 Hz, 2H), 4,59 (s, 1H), of 6.52 (d, J=8,84 Hz, 1H), PC 6.82 (m, 6N), 7,02 (m, 4H), 7,29 (m, 6N), 7,52 (d, J=2,02 Hz, 1H), 7,98 (d, J=8,84 Hz, 2H). MS high resolution calc. for C41H39ClN2O5S 706,22682 found (ERI+) 707,23370.

Example 267: 4-(3-{1-benzhydryl-5-chloro-2-[2-(2,4,6-trimethylbenzenesulfonamide)ethyl]-1H-indol-3-yl}propyl)benzoic acid/p>

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add 2-mesitylenesulfonyl procedure of example 1, step 7, when receiving the product yield 83%.1H NMR (400 MHz, CHLOROF CDCl3) δ ppm of 1.93 (m, 2H), and 2.26 (s, 3H), 2,47 (C, 6N), 2,70 (m, 4H), 2,82 (m, 2H), 2.91 in (m, 2H), 3,91 (s, 3H), 4,36 (t, J=6,44 Hz, 1H), 6,46 (d, J=8,84 Hz, 1H), 6.75 in (s, 1H), 6,79 (DD, J=8,84, and 2.27 Hz, 1H), to 6.88 (s, 2H), 7,00 (m, 4H), 7,22 (d, J=8.34 per Hz, 2H), 7,28 (m, 6N), 7,39 (d, J=2,02 Hz, 1H), 7,95 (d, J=8.34 per Hz, 2H).

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 84%.1H NMR (400 MHz, CDCl3) δ ppm of 1.94 (m, 2H), and 2.26 (s, 3H), 2,47 (C, 6N), a 2.71 (m, 4H), and 2.83 (m, 2H), 2,93 (m, 2H), 4,45 (t, J=of 5.81 Hz, 1H), 6,46 (d, J=8,84 Hz, 1H), 6.75 in (s, 1H), 6,79 (DD, J=8,97, of 2.15 Hz, 1H), to 6.88 (s, 2H), of 7.00 (m, 4H), 7,27 (m, 8H), 7,40 (d, J=2,02 Hz, 1H), 8,01 (d, J=8.34 per Hz, 2H). MS high resolution calc. for C42H41ClN2O4S 704,24756 found (ERI+) 705,25452.

Example 268: 4-(3-{1-benzhydryl-5-chloro-2-[2-({[2-fluoro-6-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid

Stage 1: 2-fluoro-6-triftoratsetilatsetonom (1.0 EQ.) add to the mixture of tetrahydrofuran (0.5 M) and diethyl ether (0.5 M) and cooled to -78°C. are added dropwise n-utility (2.5 M, 1.0 EQ.) and the reaction mixture is stirred for 40 minutes Condense the volume of sulfur dioxide, equal volume of THF and diluted with two volumes of ether. Using the cannula serves lithium salt of benzene in sulfur dioxide and the reaction mixture is allowed to slowly warm to room temperature. Remove the solvent and the resulting salt is washed with ether, then transferred to hexane (1.0 M) and cooled in a bath with ice. Add sulfurylchloride (1.06 equiv.) the reaction mixture is heated to room temperature and stirred for 5 hours. Remove the solvent, obtaining 2-fluoro-6-triftoratsetilatsetonom in the form of an oily solid white substance with a yield of 65%. The crude product is used.1H NMR (400 MHz, DMSO-D6) δ ppm 7,46 (m, 1H), 7,52 (m, 2H).

Stage 2. To methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate is added 2-fluoro-6-triftoratsetilatsetonom procedure of example 1, step 7, when receiving the product yield 62%.1H NMR (400 MHz, CDCl3) δ ppm of 1.94 (m, 2H), by 2.73 (m, 4H), 2.91 in (m, 2H), 2,99 (m, 2H), 3,91 (s, 3H), 4,87 (t, J=of 5.81 Hz, 1H), 6,50 (d, J=8,84 Hz, 1H), for 6.81 (DD, J=8,97, of 2.15 Hz, 2H), 7,03 (m, 4H), from 7.24 (d, J=8.34 per Hz, 2H), 7,30 (m, 7H), 7,41 (d, J=2,02 Hz, 1H), 7.62mm (m, 2H), 7,95 (d, J=8.34 per Hz, 2H).

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 56%.1H NMR (400 MHz, CDCl3) δ ppm to 1.96 (m, 2H), 2,75 (m, 4H), of 2.92 (m, 2H),3,00 (m, 2N), is 4.93 (t, J=5,94 Hz, 1H), 6,51 (d, J=8,84 Hz, 1H), PC 6.82 (m, 2H), 7,03 (m, 4H), 7,28 (m, 8H), 7,32 (d, J=10,61 Hz, 1H), 7,41 (d, J=2,02 Hz, 1H) 7,63 (m, 2H), 8,01 (d, J=8,08 Hz, 2H). MS high resolution calc. for [C40H33ClF4N2O4S+N] 749,18585 found 749,18578.

Example 269: 4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-fluoro-6-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate is added 2-fluoro-6-triftoratsetilatsetonom (example 268, stage 1) by the procedure of example 1, step 7, when receiving the product yield 89%.1H NMR (400 MHz, CDCl3) δ to 3.00 ppm (m, 2H), 3,12 (m, 2H), 3,20 (t, J=6,44 Hz, 2H), 3,88 (s, 3H), 4,20 (t, J=6,44 Hz, 2H), 4,99 (t, J=6,06 Hz, 1H), is 6.54 (d, J=8,84 Hz, 1H), 6,79 (d, J=8,84 Hz, 2H), at 6.84 (DD, J=8,97, of 2.15 Hz, 1H), to 6.88 (s, 1H),? 7.04 baby mortality (DD, J=6,82, 2,53 Hz, 4H), 7,28 (m, 6N), 7,33 (m, 1H), 7,54 (d, J=2,02 Hz, 1H), 7,60 (m, 2H), to 7.93 (d, J=9,10 Hz, 2H).

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 36%.1H NMR (400 MHz, CDCl3) δ ppm 3,01 (m, 2H), 3,13 (m, 2H), 3,21 (t, J=6,44 Hz, 2H), 4,22 (t, J=6,44 Hz, 2H), 5,07 (t, J=6,06 Hz, 1H), 6,55 (d, J=8,84 Hz, 1H), 6,83 (m, 3H), to 6.88 (s, 1H),? 7.04 baby mortality (m, 4H), 7,28 (m, 6N), 7,32 (m, 1H), 7,55 (d, J=2,02 Hz, 1H), to 7.61 (m, 2H), 7,98 (d, J=8,84 Hz, 2H). MS high resolution calc. for [C39H31ClF4N2O5S+N] 751,16511 found 751,16431.

Example 270: 4-{3-[1-be who Sheryl-5-chloro-2-(2-{[(2,6-dimetilfenil)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Step 1: 2,6-Dimethylbenzenesulfonamide obtained from 2-bromo-1,3-xylene the procedure of example 18, stage 1-2. The reaction yields a product in the form of a white solid with a yield of 84%.1H NMR (400 MHz, DMSO-D6) δ ppm of 2.54 (s, 6N), 6,94 (d, J=7,33 Hz, 2H), 7,02 (m, 1H).

Stage 2: methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate added 2,6-dimethylbenzenesulfonamide procedure of example 1, step 7, when receiving the product yield 66%.1H NMR (400 MHz, CDCl3) δ ppm of 1.93 (m, 2H), 2,50 (C, 6N), 2,70 (m, 4H), 2,82 (m, 2H), 2,93 (m, 2H), 3,91 (s, 3H), and 4.40 (t, J=6,32 Hz, 1H), 6,47 (d, J=8,84 Hz, 1H), 6,77 (s, 1H), 6,80 (DD, J=8,97, of 2.15 Hz, 1H), 7,00 (m, 4H), 7,07 (d, J=7,58 Hz, 2H), 7,22 (d, J=8,08 Hz, 2H), 7,27 (m, 7H), 7,40 (d, J=2,02 Hz, 1H), 7,95 (d, J=8,08 Hz, 2H).

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 96%.1H NMR (400 MHz, DMSO-D6) δ is 1.81 ppm (m, 2H) 2,50 (C, 6N), to 2.65 (m, 4H), of 2.81 (m, 2H), 2,87 (m, 2H), 6,45 (d, J=8,84 Hz, 1H), 6,77 (DD, J=8,84, and 2.27 Hz, 1H), 6,94 (s, 1H), 7,02 (m, 4H), 7,17 (d, J=7,58 Hz, 2H), 7,28 (d, J=8.34 per Hz, 2H), 7,33 (m, 6N), the 7.43 (d, J=2,27 Hz, 1H), of 7.70 (t, J=of 5.81 Hz, 1H), a 7.85 (d, J=8,08 Hz, 2H). MS high resolution calc. for [C41H-39ClN2O4S+N] 691,23919 found 691,23872.

Example 271: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimetilfenil)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-b is Sheryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate added 2,6-dimethylbenzenesulfonamide (example 270, stage 1) the procedure of example 1, step 7, when receiving the product with the release of 88%.1H NMR (400 MHz, CDCl3) δ ppm of 2.51 (s, 6N), 2,90 (m, 2H), 3,06 (m, 2H), and 3.16 (t, J=6.69 in Hz, 2H), with 3.89 (s, 3H), 4,17 (t, J=6,57 Hz, 2H), 4,50 (t, J=to 6.19 Hz, 1H), 6,53 (d, J=8,84 Hz, 1H), 6,79 (d, J=9,10 Hz, 2H), 6,83 (m, 2H), 7,02 (m, 4H), 7,06 (d, J=7,58 Hz, 2H), 7.23 percent (m, 1H), 7,28 (m, 6N), 7,53 (d, J=2,02 Hz, 1H), to 7.93 (d, J=8,84 Hz, 2H).

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 79%.1H NMR (400 MHz, DMSO-D7) δ ppm 2,48 (C, 6N), 2,85 (m, 2H), 2.95 and (m, 2H), is 3.08 (t, J=6,57 Hz, 2H), 4,15 (t, J=6, 69 Hz, 2H), 6.48 in (d, J=8,84 Hz, 1H), 6,79 (DD, J=8,84, 1.77 Hz, 1H), make 6.90 (d, J=8,84 Hz, 2H), 6,95 (s, 1H), 7,01 (m, 4H), 7,14 (d, J=7,58 Hz, 2H), 7,29 (m, 6N), 7,63 (d, J=2,02 Hz, 1H), 7,73 (t, J=5,94 Hz, 1H), 7,82 (d, J=8,84 Hz, 2H). MS high resolution calc. for [C40H37ClN2O5S+N] 693,21845 found 693,21791.

Example 272: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-diethylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Step 1: 2,6-Delibesaccompanied obtained from 2-bromo-1,3-diethylbenzene procedure of example 18, stage 1-2. The reaction yields a product in the form of solid oily pale yellow substance with a yield of 36%.1H NMR (400 MHz, DMSO-D6) δ ppm of 1.13 (t, J=7,33 Hz, 6N), is 3.08 (sq, J=7,33 Hz, 4H), of 6.96 (d, J=7,58 Hz, 2H), 7,10 (m, 1H).

Stage 2: methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate add Aut 2,6-delibesaccompanied procedure of example 1, stage 7, when receiving the product with the release of 72%.1H NMR (400 MHz, DMSO-D6) δ ppm of 1.10 (t, J=7,33 Hz, 6N), only 2.91 (m, 6N), 2,99 (m, 2H), 3,11 (t, J=6.69 in Hz, 2H), 3,81 (s, 3H), 4,18 (t, J=6.69 in Hz, 2H), of 6.49 (d, J=8,84 Hz, 1H), 6,80 (DD, J=8,84, 2,02 Hz, 1H), 6,93 (d, J=8,84 Hz, 2H), 6,97 (s, 1H), 7,02 (m, 4H), 7,17 (d, J=7,58 Hz, 2H), 7,32 (m, 5H), 7,38 (t, J=7,71 Hz, 1H), 7,65 (d, J=2,02 Hz, 1H), 7,74 (t J=5,94 Hz, 1H), a 7.85 (d, J=8,84 Hz, 2H).

Stage 3: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 88%.1H NMR (400 MHz, DMSO-D6) δ ppm of 1.10 (t, J=7,33 Hz, 6N), only 2.91 (m, 6N), 2,98 (d, J=7,83 Hz, 2H), 3,10 (t, J=6,57 Hz, 2H), 4,17 (t, J=6.69 in Hz, 2H), of 6.49 (d, J=8,84 Hz, 1H), 6,80 (DD, J=8,84, 2,02 Hz, 1H), 6,91 (d, J=a 9.09 Hz, 2H), 6,97 (s, 1H), 7,02 (m, 4H), 7,17 (d, J=7,58 Hz, 2H), 7,32 (m, 5H), 7,38 (t, J=7,58 Hz, 1H), 7,65 (d, J=2,27 Hz, 1H), 7,74 (t, J=of 5.81 Hz, 1H), 7,83 (d, J=8,84 Hz, 2H). MS high resolution calc. for [C42H41ClN2O5S+N] 721,24975 found 721,24876.

Example 273: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-diethylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate added 2,6-delibesaccompanied (example 272, step 1) by the procedure of example 1, step 7, when receiving the product with 71%yield.1H NMR (400 MHz, DMSO-D6) δ ppm of 1.11 (t, J=7,33 Hz, 6N), is 1.81 (m, 2H), 2,65 (m, 4H), 2,84 (m, 2H), 2,90 (m, 6N), of 3.84 (s, 3H), 6,44 (d, J=8,84 Hz, 1H), 6,77 (DD, J=8,84, 2,02 Hz, 1H), 6,94 (s, 1H), 702 (m, 4H), 7,19 (d, J=7,58 Hz, 2H), 7,33 (m, 7H), 7,40 (t, J=7,71 Hz, 1H), 7,43 (d, J=2,02 Hz, 1H), of 7.70 (t, J=5,68 Hz, 1H), 7,86 (d, J=8.34 per Hz, 2H).

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 85%.1H NMR (400 MHz, DMSO-D6) δ ppm of 1.11 (t, J=7,33 Hz, 6N), is 1.81 (m, 2H), 2,65 (m, 4H), 2,84 (m, 2H), 2.91 in (m, 6N), of 6.45 (d, J=8,84 Hz, 1H), 6,77 (DD, J=8,84, 2,02 Hz, 1H), 6,95 (s, 1H), 7,02 (m, 4H), 7,19 (d, J=7,58 Hz, 2H), 7,28 (d, J=8.34 per Hz, 2H), 7,33 (m, 5H), 7,40 (m, 1H), 7,43 (d, J=2,27 Hz, 1H), of 7.70 (t, J=5,68 Hz, 1H), to 7.84 (d, J=8.34 per Hz, 2H). MS high resolution calc. for [C43H43ClN2O4S+N] 719,27049 found 719,27028.

Example 274: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-acid)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: 1,3-Dimethoxybenzene (1.0 EQ.) placed in diethyl ether (0.2 M) and added dropwise n-utility (1.0 EQ.). The reaction mixture is refluxed for 3 hours. The mixture is cooled to room temperature, then placed in a bath of a mixture of dry ice and acetone and cooled to -50°C. Add the bromide (0,98 EQ.) and the reaction mixture is allowed to slowly warm to room temperature. The reaction mixture was quenched with saturated sodium thiosulfate solution and the aqueous layer was extracted with ether. The organic extracts are washed with saturated salt solution, dried over sulfate intothree and concentrate, getting a brown solid substance. The solid is subjected to recrystallization from hexane, getting the product in the form of a white solid with a yield of 27%.1H NMR (400 MHz, DMSO-D6) δ a 3.83 ppm (s, 6N), was 6.73 (d, J=8.34 per Hz, 2H), 7,30 (t, J=8.34 per Hz, 1H).

Stage 2: 2,6-Dimethoxybenzenesulfonamide obtained from 2-bromo-1,3-dimethoxybenzene procedure of example 1, stage 1. The reaction gives a mixture of sulphonylchloride and other product in the form of a white solid.

Stage 3: methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate added 2,6-dimethoxybenzenesulfonamide procedure of example 1, step 1, getting the product with the release of 72%.1H NMR (400 MHz, CDCl3) δ ppm is 3.08 (m, 2H), 3,14 (m, 2H), 3,20 (t, J=6, 69 Hz, 2H), 3,64 (C, 6N), 3,88 (s, 3H), 4,18 (t, J=6.69 in Hz, 2H), 5,41 (t, J=5,68 Hz, 1H), 6.42 per (d, J=8,84 Hz, 1H), of 6.52 (d, J=8,59 Hz, 2H), 6,79 (m, 3H), 6,91 (s, 1H), 7,02 (m, 4H), 7,25 (m, 6N), was 7.36 (t, J=8,46 Hz, 1H), 7,54 (d, J=2,02 Hz, 1H), to 7.93 (d, J=8,84 Hz, 2H), m/z (M-) 737.

Stage 4: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 100%.1H NMR (400 MHz, CDCl3) δ ppm is 3.08 (m, 2H), 3.15 in (m, 2H), 3,21 (t, J=6.69 in Hz, 2H), 3,64 (C, 6N), 4,20 (t, J=6,57 Hz, 2H), 5,44 (m, 1H), 6.42 per (d, J=8,84 Hz, 1H), 6,53 (d, J=8,59 Hz, 2H), 6,79 (DD, J=8,84, 2,02 Hz, 1H), 6,83 (d, J=8,84 Hz, 2H), 6,91 (s, 1H), 7,02 (m, 4H), 7,25 (m, 6N), was 7.36 (t, J=8,46 Hz, 1H), 7,54 (d, J=2,02 Hz, 1H), 7,98 (d, J=8,84 Hz, 2H). MS high level of the resolution calc. for [C40H37ClN2O7S+N] 725,20729 found 719,27028.

Example 275: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-acid)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: To the methyl 4-{3-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate added 2,6-dimethoxybenzenesulfonamide (example 274, stage 1) by the procedure of example 1, step 7, when receiving the product with yields of 80%.1H NMR (400 MHz, CDCl3) δ ppm1H NMR (400 MHz, CDCl3) δ ppm of 1.94 (m, 2H), 2,72 (m, 4H), 3,01 (m, 4H)and 3.59 (s, 6N), 3,91 (s, 3H), lower than the 5.37 (m, 1H), 6,37 (d, J=8,84 Hz, 1H), 6,53 (d, J=8,59 Hz, 2H), 6,76 (DD, J=8,97, of 2.15 Hz, 1H), 6,84 (s, 1H), 6,98 (m, 4H), 7,21 (d, J=8.34 per Hz, 2H), 7,26 (m, 6N), 7,38 (m, 2H), 7,94 (d, J=8.34 per Hz, 2H), m/z (M+) 737.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 91%.1H NMR (400 MHz, CDCl3) δ ppm of 1.95 (m, 2H), 2,74 (m, 4H), to 3.02 (m, 4H), 3,60 (C, 6N), 5,41 (s, 1H), 6,37 (d, J=8,84 Hz, 1H), 6,53 (d, J=8,59 Hz, 2H), 6,76 (DD, J=8,84, and 2.27 Hz, 1H), 6,84 (s, 1H), 6,99 (m, 4H), 7,25 (m, 8H), 7,37 (t, J=8,46 Hz, 1H), 7,40 (d, J=2,02 Hz, 1H), to 7.99 (d, J=8.34 per Hz, 2H). MS high resolution calc. for [C41H39ClN2O6S+N] 723,22902 found 723,22893.

Example 276: 4-[2-(1-benzhydryl-2-[(benzylmethyl)amino]ethyl}-5-nitro-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: 4-Nitroaniline (1.0 EQ.) add in a mixture of water (0.8 M) and concentrated HCl (1.8 M). To a mixture of 4:1 water and concentrated HCl (1.3 M) add monochloride iodide (1 EQ.) and cooled to 0°C. a Solution of ICl are added to a solution of aniline and the reaction mixture is left at room temperature for 20 hours. The reaction mixture is filtered, receiving iodinated product in the form of hard yellow substance with a yield of 97.3%.1H NMR (300 MHz, DMSO-D6) δ to 6.75 ppm (d, J=9,07 Hz, 1H), 7,98 (DD, J=9,07, 2,47 Hz, 1H), 8,40 (d, J=2,47 Hz, 1H), MS m/z 263 (M-H).

Stage 2: 2-Iodine-4-nitroaniline (1 EQ.) and benzhydrylamine (1.3 EQ.) add in dichloroethane (0.8 M). Add diisopropylethylamine (1.1 EQ.) and the reaction mixture is heated at 50°C for 20 hours. The reaction mixture is cooled and washed with 1 N. HCl, dried with Na2SO4and concentrate. Purification using flash chromatography (10% ethyl acetate in hexano) gives alkilirovanny product with a yield of 81%.1H NMR (400 MHz, CDCl3) δ ppm to 5.56 (d, J=4,80 Hz, 1H), 5,67 (d, J=of 5.05 Hz, 1H), 6,36 (d, J=9,10 Hz, 1H), 7,32 (m, 6N), 7,38 (m, 4H), to 7.99 (DD, J=a 9.09, of 2.53 Hz, 1H) 8,61 (d, J=2,53 Hz, 1H).

Stage 3: In a round bottom flask containing 10 ml of DMF, which was degassed with argon, add benzhydryl-(4-nitro-2-itfinal)amine (1 EQ.), methyl ester of 4-(6-hydroxydec-3-ynyloxy)benzoic acid (1.5 equiv.) LiCl (1 EQ.), COAs (5 EQ.) and palladium (II) acetate (0,04 EQ.). The reaction mixture is heated at 100°C for 7.5 hours. Then it is cooled, diluted with those who acetate, washed with water and saturated salt solution, dried over Na2SO4and concentrate, getting a brown solid substance. Purification with flash chromatography gives two products, methyl ester 4-{2-[1-benzhydryl-5-nitro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethoxy}benzoic acid methyl ester 4-{2-[1-benzhydryl-5-nitro-3-(2-hydroxyethyl)-1H-indol-2-yl]ethoxy}benzoic acid with a total yield of 71%. Products cannot be separated with flash chromatography and both are used in the next stage.1H NMR (400 MHz, CDCl3) δ ppm of 1.66 (t, J=5,56 Hz, 1H), 1,80 (t, J=5,18 Hz, 1H), 3,14 (m, 4H), to 3.35 (m, 4H), 3,81 (m, 2H), a 3.87 (m, J=l,52 Hz, 6N), 3,97 (sq, J=6,32 Hz, 2H), 4,10 (t, J=6,82 Hz, 2H), or 4.31 (t, J=to 6.19 Hz, 2H), to 6.58 (d, J=Android 4.04 Hz, 1H), 6,60 (d, J=Android 4.04 Hz, 1H), to 6.67 (d, J=9,10 Hz, 2H), 6.89 in (d, J=8,84 Hz, 2H), 7,10 (m, N), 7,20 (s, 1H), 7,32 (m, N), to 7.75 (m, 2H), of 7.90 (d, J=8,84 Hz, 2H), 7,95 (d, J=a 9.09 Hz, 2H), charged 8.52 (d, J=2,27 Hz, 1H), 8,59 (d, J=2,27 Hz, 1H).

Stage 4: the Regioisomers (1.0 EQ.) from the previous stage is transferred in THF. Add triethylamine (1.2 EQ.) and methansulfonate (1.2 EQ.). The reaction mixture is stirred until used the original substance that controls the TLC. The reaction mixture was diluted with dichloromethane and washed with water and saturated salt solution. The mixture is dried over Na2SO4and concentrate. The reaction gives a non-partial mixture of isomers with the release of 100%.1H NMR (400 MHz, CDCl3) δ of 2.81 ppm (s, 3H), 2,90 (s, 3H), at 3.35 (m, 8H), a 3.87 (m, J=l,52 Hz, 6N), 4,07(t, J=is 6.19 Hz, 2H), 4,14 (t, J=7,20 Hz, 2H), 4,30 (t, J=the 6.06 Hz, 2H), 4,49 (t, J=6.69 in Hz, 2H), 6,62 (d, J=6,57 Hz, 1H), 6,65 (d, J=6,57 Hz, 1H), 6,69 (d, J=8,84 Hz, 2H), to 6.88 (d, J=a 9.09 Hz, 2H), 7,02 (s, 1H), 7,10 (DD, J=7,71, 4,67 Hz, 8H), of 7.23 (s, 1H), 7,34 (m, N), 7,79 (m, 2H), to $ 7.91 (d, J=8,84 Hz, 2H), of 7.96 (d, J=8,84 Hz, 2H), 8,49 (d, J=2,27 Hz, 1H), to 8.62 (d, J=2,02 Hz, 1H).

Stage 5: a Mixture of the crude mesylates from the previous stage (1 EQ.) and of sodium azide (2.2 EQ.) carry in DMSO (0.05 M). The reaction mixture was stirred at room temperature until the disappearance of the original substances that control TLC. The reaction mixture was diluted with ethyl acetate, washed with water and saturated salt solution, dried over Na2SO4and concentrate getting the desired azides with quantitative yield.1H NMR (400 MHz, CDCl3) δ ppm of 3.12 (m, 4H), to 3.33 (m, 6N), to 3.64 (t, J=6,82 Hz, 2H), 3,88 (m, J=l,52 Hz, 6N), of 4.05 (t, J=6,32 Hz, 2H), 4,29 (t, J=to 6.19 Hz, 2H), 6,65 (m, 4H), 6.87 in (d, J=8,84 Hz, 2H), 7,02 (s, 1H), 7,10 (m, 8H), 7,21 (s, 1H), 7,34 (m, N), 7,78 (m, 2H), to $ 7.91 (d, J=8,84 Hz, 2H), of 7.96 (d, J=8,84 Hz, 2H), 8,49 (d, J=2,27 Hz, 1H), 8,61 (d, J=2,27 Hz, 1H).

Step 6: a Mixture of non-shared azide (1.0 EQ.) from stage 5 and triphenylphosphine (1.1 EQ.) carry in THF and stirred at room temperature until the disappearance of the original materials, obtaining a product with higher Rf by TLC data. To the reaction mixture was added 1 ml of water and continue to mix at room temperature until TLC shows the disappearance of the intermediate compounds with higher Rf. THF is dilaut in vacuum and the resulting solid is transferred into ethyl acetate, washed with water and saturated salt solution, dried over Na2SO4and concentrate. Purification with flash chromatography gives the total yield of recovered product, equal to 43%. The regioisomers separated using flash chromatography (gradient elution from 0.25% methanol in dichloromethane to 10% methanol in dichloromethane). The regioisomers identify the NMR and the desired compound, methyl ester 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-nitro-1H-indol-3-yl]ethoxy}benzoic acid are selected for the next stage.1H NMR (400 MHz, CDCl3) δ ppm 3,30 (m, 6N), 3,88 (s, 3H), 4,27 (t, J=6,57 Hz, 2H), 6,56 (d, J=a 9.35 Hz, 1H), to 6.88 (d, J=9,10 Hz, 2H), 7,10 (DD, J=6,44, 2.65 Hz, 4H), 7,32 (m, 7H), 7,72 (DD, J=a 9.09, of 2.27 Hz, 1H), 7,95 (d, J=8,84 Hz, 2N), at 8.60 (d, J=2,27 Hz, 1H). MS m/z 550 (M+).

Step 7: methyl ether of 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-nitro-1H-indol-3-yl]ethoxy}benzoic acid add α-toluensulfonate procedure of example 1, step 7, when receiving the product yield 61%.1H NMR (400 MHz, CDCl3) δ ppm 2,89 (m, 2H) 3,09 (m, 2H), 3,25 (t, J=the 6.06 Hz, 2H), 3,88 (s, 3H), 4.09 to (s, 2H), 4,15 (m, 1H), 4,25 (t, J=the 6.06 Hz, 2H), is 6.61 (d, J=a 9.35 Hz, 1H), at 6.84 (d, J=8,84 Hz, 2H), 6,97 (s, 1H), 7,07 (m, 4H),7,20 (m, J=8,08, of 1.52 Hz, 2H), 7,32 (m, N), to 7.77 (DD, J=9,10, and 2.27 Hz, 1H), 7,95 (d, J=9,10 Hz, 2H), 8,59 (d, J=2,27 Hz, 1H). MS m/z 703 (M-N).

Stage 8: the Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with the output of the m to 75%. 1H NMR (400 MHz, CDCl3) δ ppm 2,90 (m, 2H), 3,10 (m, 2H), 3,26 (t, J=the 6.06 Hz, 2H), 4,10 (s, 2H), 4.26 deaths (t, J=the 6.06 Hz, 2H), 4,37 (t, J=to 6.19 Hz, 1H), is 6.61 (d, J=a 9.35 Hz, 1H), 6,85 (d, J=a 9.09 Hz, 2H), 6,97 (s, 1H), 7,07 (m, 4H), 7,20 (m, 2H), 7,32 (m, N), 7,76 (DD, J=9,10, and 2.27 Hz, 1H), of 7.97 (d, J=8,84 Hz, 2H), 8,58 (d, J=2,27 Hz, 1H). MS high resolution calc. for C39H35N3O7S 689,2196 found (ERI+) 690,22581.

Example 277: 4-{2-[1-benzhydryl-5-chloro-2-{2-[({2-(2-chloro-1-methylethyl)benzene}sulfonyl)amino]ethyl}-1H-indol-3-yl]propyl}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) is added 2-(2-chloro-1-methylethyl)benzosulphochloride procedure of example 1, step 7, when receiving the product with the release of 65%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 100%. MS high resolution calc. for [C42H40Cl2N2O4S+N] 739,21586 found 739,21611.

Example 278: 4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(2-chloro-1-methylethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 2-(2-chloro-1-methylethyl)benzosulfimide procedure of example 1, step 7 exit 61%.

Stage 2: Intermediate Obedinenie, representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 90%. m/z (M-1)=739,3.

Example 279: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 2,6-dimethylbenzenesulfonamide procedure of example 1, stage 7 output 45%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 88%. m/z (M-1)=738,2.

Example 280: 4-[3-(1-benzhydryl-5-chloro-2-{2-[(cyclopropylmethyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and cyclopropanesulfonyl procedure of example 1, step 7 exit 83%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 80%. MS high resolution calc. for C36H35ClN2O4S 626,2006 found (ERI+) 627,20734.

Example 281: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-phenylethyl)sulfonyl]am is but}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: To the methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) add phenylethanolamine (receive, following the procedure J.Org.Chem. 1984, 49, 5124-5131) by the procedure of example 1, step 7, when receiving the product yield of 77%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 82%. MS high resolution calc. for C41H-39ClN2O4S 690,2313 found (ERI+) 691,2383.

Example 282: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-phenylethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and phenylethanolamine procedure of example 1, step 7 exit 81%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 85%. MS high resolution calc. for C40H37ClN2O5S 692,2115 found (ERI+) 693,2185.

Example 283: 3-(2-(1-benzhydryl-5-chloro-2-(2-(phenylmethylsulfonyl)ethyl)-1H-indol-3-yl)ethoxy)benzoic acid

Stage 1: the Crude 2-{1-benzhydryl-2-[2-(tert-butyldiphenylsilyl)ethyl]-5-chloro-1H-indol-3-yl}ethanol from the article is Hai 6 example 143 treated with methyl ether 3-hydroxybenzoic acid by the procedure of example 143, stage 8, receiving the desired methyl ester 3-(2-{1-benzhydryl-2-[2-(tert-butyldiphenylsilyl)ethyl]-5-chloro-1H-indol-3-yl}ethoxy)benzoic acid with a yield of 85%.

Stage 2: Connection with the removed protection get the procedure described in example 143, step 9. The crude methyl ester of 3-{2-[1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethoxy}benzoic acid directly used in the next stage without additional purification.

Stage 3-5: Methyl ester of 3-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoic acid obtained by the procedure described in example 147, stage 3-7 exit 57% (for stage 3).

Step 6: methyl ether 3-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoic acid add α-toluensulfonate procedure of example 1, step 7, when receiving the product yield was 73%.

Stage 7: the Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 88%. MS high resolution calc. for [C39H35ClN2O5S+N] 679,2028 found 679,2029.

Example 284: 3-(2-(1-benzhydryl-5-chloro-2-(2-(3,4-dichlorophenyl)methylsulfonylamino)ethyl)-1H-indol-3-yl)ethoxy)benzoic acid

Stage 1: To the methyl ether of 3-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoic acid (stage , example 283) add 3,4-dichlorobenzenesulfonate procedure of example 1, step 7, when receiving the product yield 84%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 91%. MS high resolution calc. for [C39H33Cl3N2O5S+N] 747,12486 found 747,12423.

Example 285: 3-{2-[1-benzhydryl-5-chloro-2-(2-phenylmethanesulfonyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: the Crude 2-{1-benzhydryl-2-[2-(tert-butyldiphenylsilyl)ethyl]-5-chloro-1H-indol-3-yl}ethanol from stage 6, example 143 treated with methyl ether 2-hydroxybenzoic acid by the procedure of example 143, step 8, receiving the desired methyl ether 2-(2-{1-benzhydryl-2-[2-{tert-butyldiphenylsilyl)ethyl]-5-chloro-1H-indol-3-yl}ethoxy)benzoic acid with the release of 60%.

Stage 2: Connection with the removed protection get the procedure described in example 143, step 9. The crude methyl ester of 2-{2-[1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethoxy}benzoic acid directly used in the next stage without additional purification.

Stage 3-5: Methyl ester of 2-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoic acid obtained by the procedure described in example 147, stage 3-7 with the release of 60% (3 is tdii).

Step 6: methyl ether 2-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoic acid and add-toluensulfonate procedure of example 1, step 7, when receiving the product with the release of 90%.

Stage 7: the Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 90%. MS high resolution calc. for [C39H35ClN2O5S+H] 679,2028 found 679,20358.

Example 286: 3-(2-{1-benzhydryl-5-chloro-2-[2-(3,4-dichlorobenzenesulfonyl)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Stage 1: To the methyl ether of 2-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoic acid (step 5, example 281) add 3,4-dichlorobenzenesulfonate procedure of example 1, step 7, when receiving the product yield 84%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 89%. MS high resolution calc. for [C39H33Cl3N2O5S+H] 747,12486 found 747,12457.

Example 287: 4-[2-(1-benzhydryl-5-chloro-2-{2-[({[(2,4-dichlorophenyl)sulfanyl]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: To the methyl 4-{2-[1-benzhydryl-5-chloro-2-(2-chloromethanesulfonyl)-1H-indol-3-yl]the toxi}benzoate, example 81, step 1, add 2,4-Dichlorotoluene procedure of example 81, step 2. The crude substance is purified preparative HPLC to yield 50%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 100%. m/z (M-1) 776,92.

Example 288: 4-[2-(1-benzhydryl-5-chloro-2-{2-[({[(2,4-differenl)thio]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: To the methyl 4-{2-[1-benzhydryl-5-chloro-2-(2-chloromethanesulfonyl)-1H-indol-3-yl]ethoxy}benzoate, example 81, step 1, add 2,4-diversional procedure of example 81, step 2. The crude substance is purified preparative HPLC to yield 27%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 100%. m/z (M-1) 744,97.

Example 289: 4-[2-(1-benzhydryl-5-chloro-2-{2-[({[(3,4-dichlorophenyl)sulfinil]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid

Stage 1: Methyl 4-[2-(1-benzhydryl-5-chloro-2-{2-[({[(3,4-dichlorophenyl)thio]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoate (step 1 of example 219) in THF oxidize msrv (1.1 EQ.). The crude substance is purified column flash chromatography using a mixture of 30% EtOAc/hexane to yield 42%.

Stage 2: Prohm is filling connection, representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 93%. m/z (M-1) 795,14.

Example 290: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-hydroxyphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: Hydronaut 4-[2-(1-benzhydryl-5-chloro-2-{2-[2-(2-methylpentan-2,4-vinyloxy)benzosulfimide]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid (0.55 g, 0.70 mmol) (step 1, example 183) and 10% Pd/C (55 mg) in MeOH (30 ml) and EtOH (20 ml). The resulting mixture is filtered through celite and concentrated. The residue is subjected to chromatography using a mixture of 35-40% EtOAc/hexane, obtaining the desired product (0.50 g, 95%).

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 90%. MS high resolution calc. for C38H33ClN2O6S 680,1748 found (ERI+) 681,18118.

Example 291:N-{2-[1-benzhydryl-5-chloro-3-(2-{4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ilidene)methyl]phenoxy}ethyl)-1H-indol-2-yl]ethyl}-1-(3,4-dichlorophenyl)methanesulfonamide

Stage 1: 2-{1-benzhydryl-2-[2-(tert-butylbiphenyl-silyloxy)ethyl]-5-chloro-1H-indol-3-yl}ethanol (step 6, example 142) is combined with 4-hydroxybenzaldehyde under the conditions described in example 189, step 1, receiving 4-(2-{1-benzhydryl-2-[2-(tert-butyl is fenilsalicilata)ethyl]-5-chloro-1H-indol-3-yl}ethoxy)benzaldehyde with a yield of 70%.

Stage 2: Remove protection from silyl ether from the previous stage, following the procedure of example 143, step 9, receiving 4-{2-[1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethoxy}benzaldehyde with the release of 90%.

Stage 3: the Alcohol from the previous stage trigger metamorphosis in mesilate, as described in stage 10 of example 143, getting the desired mesilate, which is used in the next stage without purification.

Stage 4: Mesilate from the previous stage is treated under the conditions described in stage 11 of example 143, receiving 4-{2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzaldehyde with exit 98% (in two stages).

Stage 5: a Mixture of 4-{2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzaldehyde (1.29 g, is 2.41 mmol, 1.0 EQ.), 2,4-thiazolidinedione (0,41 g of 3.13 mmol, 1.3 EQ.) and piperidine (0,12 ml of 1.21 mmol, 0.5 EQ.) in EtOH (125 ml) is refluxed overnight. EtOH is removed under vacuum. The residue was diluted with EtOAc and washed with water, then with saturated salt solution. The organic layer is dried over MgSO4and concentrated and the residue is subjected to chromatography using a mixture of 30-35% EtOAc/hexane, receiving 5-(4-{2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzylidene)thiazolidine-2,4-dione (1,33 g, 87%).

Step 6: To a solution of the product from stage 5 in THF (80 ml) in small portions add Ph3P. the Mixture is stirred for 1 day. Add 3 m the water and stirred for additional 2 days. Filtered the obtained solid substance, which identify LC/MS as triphenylphosphine the above azide (60%).

Stage 7: Imin (250 mg, 0.29 mmol, 1.0 EQ.) from stage 6 and (3,4-dichlorophenyl)methylsulfonylmethyl in a mixture of CH2Cl2(10 ml) and saturated NaHCO3(5 ml) is stirred over night procedure of example 1, step 7, when receiving the product with the release of 7%. m/z (M-1) 830,45.

Example 292 N-[2-(1-benzhydryl-5-chloro-3-{2-[4-(2,4-dioxothiazolidine-5-ylidenemethyl)phenoxy]ethyl}-1H-indol-2-yl]ethyl}-2-methylbenzenesulfonamide

Stage 1: a Mixture of triphenylphosphine (300 mg, 0.35 mmol, 1.0 EQ.) from stage 6 of example 287 2-methylbenzenesulfonamide in a mixture of CH2Cl2(15 ml) and saturated NaHCO3(5 ml) is stirred over night procedure of example 1, step 7, when receiving the product with the release of 3%. MS high resolution calc. for [C42H36ClN3O5S-H] 760,1723 found 760,1728.

Example 293: 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(1-methyl-1H-imidazol-2-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: To the methyl 4-{3-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (step 6, example 42) was added 1-methyl-1H-imidazol-2-sulphonylchloride procedure of example 1, step 7, when receiving the product yield 70%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 when the EPA 1, receiving specified in the header of the acid with a yield of 92%. MS high resolution calc. for [C37H35ClN4O4S+H] 667,2141 found 667,2137.

Example 294: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(1-methyl-1H-imidazol-2-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Stage 1: This compound is obtained from methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (step 6, example 1) and 1-methyl-1H-imidazol-2-sulphonylchloride procedure of example 1, step 7, when receiving the product yield 76%.

Stage 2: Intermediate connection representing an ester, hydrolyzing in accordance with the stage 8 of example 1, obtaining specified in the header of the acid with a yield of 87%. MS high resolution calc. for [C36H33ClN4O5S+H] 669,1933 found 669,1933.

Example 295: 4-{3-[1-benzhydryl-2-(2-{[(2-chlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Stage 1: a Mixture of methyl-4-identity (5.3g, a 20.2 mmol), allyl alcohol (1.78 g, 30.3 mmol), NaHCO3(4,24 g, and 50.5 mmol), Pd(OAc)2(0.14 g, of 0.60 mmol), (n-Bu)4NBr (6,55 g, a 20.2 mmol) and molecular sieves 4 Å (4.1 g) in anhydrous DMF (69 ml) was stirred at room temperature for 4 days. The reaction mixture was filtered through celite, the filtrate was poured into water and extracted with EtOAc. The organic layer was washed with saturated salt solution, dried (Na2SO4 ) and concentrated in vacuo. Flash chromatography (silica gel, 10-20% EtOAc/hexane) gives 2,11 g (85% restored original substance) of the desired methyl ester 4-(3-oxopropyl)benzoic acid as a transparent oily substance.

Stage 2: To a solution of 2-methyl-1H-indole (0,86 g, 5.2 mmol) and methyl ester of 4-(3-oxopropyl)benzoic acid (1.0 g, 5.2 mmol) in methylene chloride (50 ml) is added TFU (1.78 g, 15.6 mmol), followed by the addition of triethylsilane (1,81 g, 15.6 mmol). The reaction mixture was stirred overnight, quenched with saturated solution of NaHCO3(50 ml) and the organic layer was washed with a saturated solution of NaHCO3, water, saturated salt solution and dried (Na2SO4). The solvent is removed under reduced pressure and the residue purified column flash chromatography using a mixture of 10-20% EtOAc/hexane, getting the desired methyl ester 4-[3-(2-methyl-1H-indol-3-yl)propyl]benzoic acid with a yield of 88% (1,67 g).

Stage 3: To a solution of the product from the previous stage 2 (1.66 g, a 4.86 mmol) in DMF (20 ml) is added NaH (60% in mineral oil, 0.24 g, 5.83 mmol) in an atmosphere of N2. The mixture is stirred for 1 hour at room temperature, then added dropwise to benzhydrylamine (1.8 g, 7,29 mmol) in DMF (5 ml). This reaction mixture is stirred over night at room temperature. To the reaction cosiderable water (500 ml) and extracted with EtOAc, washed with saturated salt solution, dried (Na2SO4) and concentrate under reduced pressure to a brown syrup, which was purified by chromatography on silica gel using a mixture of 10% EtOAc/hexane as eluent to highlight methyl ester 4-[3-(1-benzhydryl-2-methyl-1H-indol-3-yl)propyl]benzoic acid as white solid with a yield of 76% (1.47 g).

Stage 4: the Product from the preceding stage (1,46 g, 2,87 mmol) dissolved in CCl4(14,5 ml), then added NBS (1,02 g, 5,73 mmol) and benzoyl peroxide (2 mg). The reaction mixture is refluxed for 1 hour (until you disappear all the original substance). This mixture is cooled to room temperature, filtered and the solid is washed with CCl4. The filtrate is evaporated to a brown residue, which is dissolved in a mixture of acetone (40 ml) and water (4 ml), then to this solution was added Ag2CO3(1,75 g, and 3.16 mmol) and after stirring over night at room temperature, it is filtered through celite, the solvent is evaporated under reduced pressure and to the residue water is added. The mixture is extracted with EtOAc, washed with saturated salt solution, dried (Na2SO4) and evaporated to a syrup, which is cleaned with a mixture of 10% EtOAc/hexane, highlighting methyl ester 4-[3-(1-benzhydryl-2-formyl-1H-indol-3-yl)propyl]benzoic acid (1.13 g) with a yield of 8%. Alternatively, the dibromide from the reaction with N-bromosuccinimide you can pour in DMSO (10-20% concentration by weight) and stirred for 30 minutes at room temperature. After completion of the reaction, the reaction mixture was poured into water and the resulting precipitate was separated by filtration, the filter cake washed with water and dried, obtaining essentially quantitative yield.

Stage 5: To a solution of the indole from the previous stage (0.52 g, 1 mmol) in CH3NO2(6.2 ml) is added NH4OAc (0,077 g, 1 mmol), the mixture is refluxed for 1 hour, then add the NH4OAc (0,077 g, 1 mmol), the mixture continue to boil under reflux for an additional 1 hour, again add NH4OAc (0,077 g, 1 mmol) and continue heating for an additional 1 hour. The reaction mixture is allowed to cool to room temperature, add EtOAc (50 ml), then add 100 ml of water. The aqueous layer was extracted with EtOAc and the combined organic layers washed with saturated salt solution, dried (Na2SO4) and evaporated to education yellow foam, which is subjected to chromatographic purification using a mixture of 10% EtOAc/hexane as eluent, obtaining the methyl ester of 4-{3-[1-benzhydryl-2-(2-nitrovinyl)-1H-indol-3-yl]propyl}benzoic acid as a yellow foam with a yield of 75% (range 0.38 g).

Stage 6: Zn(Hg) receive, EXT is vlaa HgCl 2(3.4 g, 7.2 mmol) to a mixture of Zn dust (34,68 g, 530,35 mmol) and 5% HCl (38 ml) in a 100 ml flask, and the mixture vigorously stirred for 10 minutes Decanted aqueous phase, again add 38 ml of 5% HCl and the mixture is stirred for 10 minutes the Aqueous phase is decanted. This solid is added to the vinyl nitrosoaniline 6 (15 g, 26,57 mmol) in THF (660 ml) and concentrated HCl (64,5 ml). This mixture is stirred at room temperature for 1 hour, then refluxed for 15 minutes, the Reaction mixture was cooled to room temperature and filtered through celite. To the filtrate is added an aqueous solution of NH4OH (200 ml), stirred for 15 min and the THF removed under reduced pressure. The aqueous layer was extracted with CH2Cl2combined organic layer was washed with saturated salt solution, dried (Na2SO4) and concentrated to a brown foam, which is purified column chromatography, first elwira column CHCl3to remove non-polar impurities, then with a mixture of 2% MeOH/CHCl3to select the desired methyl ester 4-{3-[2-(2-amino-ethyl)-1-benzhydryl-1H-indol-3-yl]propyl}benzoic acid with a yield of 40% (6,1 g).

Stage 7: The amine (1.0 EQ.) and saturated NaHCO3(0,14 M) in CH2Cl2(0,07 M) add 2-chlorobenzenesulfonamide (1.0 EQ.). After 1 hour the mixture was poured into a saturated solution b is sodium carbonate and extracted with CH 2Cl2. The combined organic phase was washed with saturated salt solution, dried over sodium sulfate and purified column chromatography, receiving 92% of the desired methyl ester 4-(3-{1-benzhydryl-2-[2-(2-chlorobenzenesulfonamide)ethyl]-1H-indol-3-yl}propyl)benzoic acid.

Stage 8: the resulting ester is subjected to hydrolysis, stirring with 1 N. NaOH (5 EQ.) in THF (0,07 M) and a sufficient amount of MeOH to obtain a clear solution. Reaction control TLC (10% MeOH-CH2Cl2) on the extinction of the original substance. The mixture is stirred over night at room temperature and then concentrated, diluted with H2O and acidified to pH 2-4, using 1M HCl. The aqueous phase is extracted with EtOAc and the organic phase is washed with saturated salt solution, dried over sodium sulfate and concentrated, obtaining mentioned in the title compound with a yield of 56%. m/z (M-1) 663,2.

Example 296: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-Formentera acid

Stage 1: [(3,4-dichlorophenyl)methyl]sulphonylchloride (0.07 g, 0.24 mmol) was added with stirring to a mixture of ethyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}-2-perbenzoate (step 6, example 190, 0.17 g, 0.2 mmol) and K2CO3(by 0.055 g, 0.4 mmol) in a mixture of CH2Cl2(2 ml) and water (0.7 ml). After 2 hours at room is the temperature of the mixture is extracted with CH 2Cl2(10 ml) and the extract washed with 0.5 N. NaOH, saturated salt solution and dried over sodium sulfate. A solution of CH2Cl2filtered through silica gel and the filtrate is evaporated. The resulting residue is triturated in a mixture of ether and hexane, obtaining 0.15 g of ethyl 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino)ethyl)-1H-indol-3-yl]ethoxy}-2-perbenzoate in the form of a white solid; Tpl.=83-85°C; MS high resolution calc. for C41H-36Cl3FN2O5S 792,1395 found (ERI+) 793,14729.

Step 2: Ethyl 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino)ethyl)-1H-indol-3-yl]ethoxy}-2-perbenzoate (0.11 g, 0.14 mmol), THF (0.5 ml), MeOH (0.5 ml) and 1 N. NaOH (0.5 ml) is stirred together overnight. Remove the solvents and the resulting residue move in the water. The solution is acidified with 1 N. HCl and extracted with ethyl acetate. The extract is dried over sodium sulfate and evaporated. The resulting residue is triturated in a mixture of ether and hexane, obtaining 0.10 g of 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino)ethyl)-1H-indol-3-yl]ethoxy}-2-fermenting acid in the form of a white solid; TPL=117-119°C; MS high resolution calc. for C39H32Cl3FN2O5S 764,1082 found (ERI+) 787,09794.

Example 297: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-Chlorobenzyl)sulfonyl]amino}et is l)-1H-indol-3-yl]ethoxy}-2-Formentera acid

Stage 1: [(2-chlorophenyl)methyl]sulphonylchloride (0.14 g, 0.6 mmol) was added with stirring to a mixture of ethyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}-2-perbenzoate (step 6, example 190, 0.12 g, 0.2 mmol) and K2CO3(0.11 g, 0.8 mmol) in a mixture of CH2Cl2(2 ml) and water (1 ml). After 2 hours at room temperature the mixture is extracted with CH2Cl2(10 ml) and the extract washed with 0.5 N. NaOH, saturated salt solution and dried over sodium sulfate. A solution of CH2Cl2filtered through silica gel and the filtrate is evaporated. The resulting residue is triturated in a mixture of ether and hexane, obtaining 0.07 g of ethyl 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-Chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-perbenzoate in the form of a white solid.

Step 2: Ethyl 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-Chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-perbenzoate (0.06 g, 0.1 mmol), THF (0.5 ml), MeOH (0.5 ml) and 1 N. NaOH (0.5 ml) is stirred together overnight. Remove the solvents and the resulting residue move in the water. The solution is acidified with 1 N. HCl and extracted with ethyl acetate. The extract is dried over sodium sulfate and evaporated. The resulting residue is triturated in a mixture of ether and hexane, obtaining 0.06 g of 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-Chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-fermenting acid in the form of a solid is razno-white matter; TPL=132-135°C; MS (ERIE) m/z 729,74 ((M-H) -); - MS high resolution calc. for C39H33Cl2FN2O5S 730,1471 found (ERI+) 731,15514.

Example 298: 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]-2,2-dimethylpropanoate acid

Stage 1: [(3,4-chlorophenyl)methyl]sulphonylchloride (0.06 g, 0.2 mmol) was added with stirring to a mixture of ethyl 3-(4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]econsultancy}phenyl)-2,2-dimethylpropionic (0.09 g, 0.14 mmol) and K2CO3(0.04 g, 0.28 mmol) in a mixture of CH2Cl2(2 ml) and water (0.7 ml). After 2 hours at room temperature the mixture is extracted with CH2Cl2(10 ml) and the extract washed with 0.5 N. NaOH, saturated salt solution and dried over sodium sulfate. A solution of CH2Cl2filtered through silica gel and the filtrate is evaporated. The resulting residue is triturated in a mixture of ether and hexanol, receiving 0.04 g of ethyl 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]-2,2-dimethylpropanoate in the form of a white solid.

Step 2: Ethyl 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]-2,2-dimethylpropanoate (0.04 g, 0.05 mmol), THF (0.5 ml), MeOH (0.5 ml) and 1 N. NaOH (0.5 ml) is stirred over night. Remove the solvent and obtained the resulting residue move in the water. The solution is acidified with 1 N. HCl and extracted with ethyl acetate. The extract is dried over sodium sulfate and evaporated. The resulting residue is triturated in a mixture of ether and hexanol, receiving 0.04 g of 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]-2,2-dimethylpropanoate acid in the form of a white solid; TPL=207-208°C; MS (ERIE) m/z 849,1 (M-H); MS high resolution calc. for C43H41Cl3N2O6S2850,1472 found (ERI+) 851,1545.

Example 299: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-methoxybenzoic acid

Stage 1: Methyl ether of 2,4-dihydroxybenzoic acid (11,76 g, 70 mmol) was dissolved in Et2O (175 ml). Then add Et3N (10,78 ml, 77 mmol), Ac2O (7,28 ml, 77 mmol) and DMAP (catalytic amount). Then the reaction solution is stirred for one hour at room temperature. Then the reaction solution is concentrated on a rotary evaporator and the resulting residue purified on a column of silica gel using dichloromethane as eluent. Get 3,44 g of methyl ester of 4-acetoxy-2-hydroxybenzoic acid with a yield of 23%.

Stage 2: To a mixture of the product from stage 1 (0,962 g, 4.6 mmol), Ph3P (1,79 g, 6.8 mmol) and dichloromethane (10 ml) was added MeOH (0.3 ml, 7.4 mmol). Then p is a promotional mix add DEAD (1,32 ml, 8.4 mmol). The reaction mixture was stirred at room temperature for 4 days. The reaction solution is concentrated on a rotary evaporator and the resulting residue purified on silikagelevye preparative plates using a mixture of 1:3 EtOAc/hexane as eluent. Obtain 1.10 g of methyl ester of 4-acetoxy-2-methoxybenzoic acid with a quantitative yield.

Stage 3: To a solution of the product from stage 2 (1.10 g, 4.9 mmol) in a mixture of THF (1 ml) and MeOH (1 ml) is added 0.1 G. of NaOH (10 ml, 1 mmol). The reaction mixture is stirred for three days at room temperature. The reaction solution is concentrated on a rotary evaporator and the resulting residue is dissolved in water. The solution is neutralized 1 N. HCl, and precipitation. Collect the precipitate and washed with water and hexane. Get to 0.29 g of methyl ester of 4-hydroxy-2-methoxybenzoic acid with a yield of 33%.

Stage 4: To a mixture of methyl ester of 4-hydroxy-2-methoxybenzoic acid (to 0.29 g, 1.6 mmol), Ph3P (0.312 g, 1.2 mmol) and dichloromethane (10 ml) is added 2-{1-benzhydryl-2-[2-(tert-butyldiphenylsilyl)ethyl]-5-chloro-1H-indol-3-yl}ethanol (step 6, example 142, 0,503 g, 0.78 mmol). Then to the reaction mixture are added DEAD (0.2 ml, 1.3 mmol). The reaction mixture was stirred at room temperature overnight. The reaction solution is concentrated on a rotary evaporator and the scientists in the residue purified on silikagelevye preparative plates, using dichloromethane as eluent. Obtain 0.25 g of methyl ester of 4-(2-{1-benzhydryl-2-[2-(tert-butyldiphenylsilyl)ethyl]-5-chloro-1H-indol-3-yl}ethoxy)-2-methoxybenzoic acid with a yield of 40%.

Stage 5: To a solution of methyl ester 4-(2-{1-benzhydryl-2-[2-(tert-butyldiphenylsilyl)ethyl]-5-chloro-1H-indol-3-yl}ethoxy)-2-methoxybenzoic acid (0.25 g, 0.31 mmol) in THF (4 ml) was added TBAF (1M in THF) (0,37 ml of 0.37 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction solution is concentrated on a rotary evaporator and the resulting residue purified on silikagelevye preparative plates using a mixture of 1:9 EtOAc/dichloromethane as eluent. Obtain 0.11 g of methyl ester of 4-{2-[1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethoxy}-2-methoxybenzoic acid (white solid) with a yield of 62%.

Step 6: To a solution of the alcohol from stage 5 (0.11 g, 0,19 mmol) in dichloromethane (8 ml) at 0°add MeSO2Cl (0,03 ml to 0.39 mmol) and Et3N (of 0.07 ml, 0.48 mmol). The reaction mixture was stirred at 0°C for 1 hour and then warmed to room temperature and stirred for an additional hour. The reaction solution is concentrated on a rotary evaporator. Get 0,123 g of methyl ester of 4-{2-[1-benzhydryl-5-chloro-2-(2-methanesulfonylaminoethyl)-1H-indol-3-yl]ethoxy}-2-what ethoxybenzoyl acid with a quantitative yield.

Stage 7: Mesilate from the previous stage (0,123 g 0,19 mmol) dissolved in DMF (5 ml). Add NaN3(0,065 g, 1.0 mmol), the mixture is heated to 60°C and stirred for 3 hours. The reaction mixture is cooled to room temperature and add water. Extracted with EtOAc and the organic layer was washed with a saturated solution of salt. The organic layer is dried over sodium sulfate, filtered and concentrated on a rotary evaporator. Additionally dried under a strong vacuum. Get 0,110 g of methyl ester of 4-{2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}-2-methoxybenzoic acid with a yield of 97%.

Step 8: To a solution of azide from stage 7 (0,110 g, 0.18 mmol) in THF (2 ml) add Ph3P (polymeric carrier: 3 mmol Ph3P/gram) (0,110 g, 0.33 mmol). The reaction mixture was stirred at room temperature for 24 hours. Then add water (0.5 ml) and the reaction mixture was stirred at room temperature overnight. The reaction solution is filtered and the filtrate concentrated on a rotary evaporator. The resulting residue is purified on silikagelevye preparative plates using 2% MeOH in dichloromethane as eluent. Get 0,012 g of methyl ester of 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}-2-methoxybenzoic acid with a yield of 12%.

Step 9: To a solution of amine from stage 8 (0,012 g, 0,mol) and [(3,4-dichlorophenyl)methyl]sulphonylchloride (0,010 g, 0,039 mmol) in dichloromethane (2 ml) is added aqueous saturated solution of Na2CO3(2 ml). The reaction mixture was stirred at room temperature for two hours. Then the reaction solution is separated, the organic phase is collected, washed with saturated salt solution and dried over sodium sulfate. The organic solution is filtered and concentrated on a rotary evaporator. The resulting residue is purified on silikagelevye preparative plates using 2% MeOH in dichloromethane as eluent. Get to 0.016 g of the desired sulfonamida (white solid) with a yield of 96%. m/z (M+1) 793.

Step 10: To a solution of ester from stage 9 (0,016 g, at 0.020 mmol) in a mixture of THF (1 ml) and MeOH (1 ml) was added 1 N. NaOH (1 ml). The reaction mixture was stirred at room temperature for 5 days. THF and MeOH is removed on a rotary evaporator. Extracted with dichloromethane, separated and concentrate the aqueous layer. The water layer is neutralized 1 N. HCl and collect the resulting precipitate. Get 0,013 g indicated in the title acid (solid yellow substance) with the release of 84%. m/z (M-1) 777.

Example 300: 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-isopropoxybenzoic acid

Step 1: To a mixture of methyl ester of 4-acetoxy-2-methoxybenzoic acid (step 1, example 299, 1.18 g, 5.6 mmol), Ph3P (1.84 g, 7 mmol) and dichloromethane (15 ml) is added isopropanol (0.63 ml, 8,2 mmol). Then to the reaction mixture are added DEAD (1,12 ml, 7.1 mmol). The reaction mixture was stirred at room temperature for 2 days. The reaction solution is concentrated on a rotary evaporator and the resulting residue purified on silikagelevye preparative plates using a mixture of 1:5 EtOAc/hexane as eluent. Get 1,11 g of methyl ester of 4-acetoxy-2-isopropoxybenzoic acid with a yield of 79%.

Stage 2: To a solution of methyl ester 4-acetoxy-2-isopropoxybenzoic acid (0.910 g, 3.6 ml) in a mixture of THF (1 ml) and MeOH (1 ml) is added 0.1 G. of NaOH. The reaction mixture is stirred for 3 days at room temperature. The reaction solution is concentrated on a rotary evaporator and the resulting residue is dissolved in water. The solution is neutralized 1 N. HCl and a precipitate. The precipitate is collected and washed with water and hexane. Get 0,870 g of methyl ester of 4-hydroxy-2-isopropoxybenzoic acid with a quantitative yield.

Stage 3: To a mixture of methyl ester of 4-hydroxy-2-isopropoxybenzoic acid (0,328 g, 1.6 mmol), Ph3P (0.312 g, 1.2 mmol) and dichloromethane (10 ml) is added 2-{1-benzhydryl-2-[2-(tert-butyldiphenylsilyl)ethyl]-5-chloro-1H-indol-3-yl}ethanol (step 6, example 142, 0,500 g, 0.78 mmol). Then to the reaction mixture are added DEAD (0.2 ml, 1.3 mmol). The reaction mixture was stirred at ControlTemplate during the night. The reaction solution is concentrated on a rotary evaporator and the resulting residue purified on silikagelevye preparative plates using dichloromethane as eluent. Obtain 0.20 g of methyl ester of 4-(2-{1-benzhydryl-2-[2-(tert-butyldiphenylsilyl)ethyl]-5-chloro-1H-indol-3-yl}ethoxy)-2-isopropoxybenzoic acid with a yield of 31%.

Stage 4: To a solution of silyl ether from stage 3 (0.20 g, 0.24 mmol) in THF (4 ml) was added TBAF (1 M in THF) (to 0.29 ml, 0.29 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction solution is concentrated on a rotary evaporator and the resulting residue purified on silikagelevye preparative plates using a mixture of 1:9 EtOAc/dichloromethane as eluent. Obtain 0.10 g of methyl ester of 4-{2-[1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethoxy}-2-isopropoxybenzoic acid (brown solid substance) to yield 70%.

Stage 5: To a solution of the alcohol from stage 4 (0.10 g, 0,17 mmol) in dichloromethane (8 ml) at 0°With add methanesulfonanilide (0,03 ml to 0.39 mmol) and Et3N (0.06 ml, 0.43 mmol). The reaction mixture was stirred at 0°C for 1 hour and then warmed to room temperature and stirred for an additional hour. The reaction solution is concentrated on a rotary evaporator. Get 0,115 g of methyl ester of 4-{-[1-benzhydryl-5-chloro-2-(2-methanesulfonylaminoethyl)-1H-indol-3-yl]ethoxy}-2-isopropoxybenzoic acid with a quantitative yield.

Stage 6: Mesilate from stage 5 (0,115 g, 0,17 mmol) dissolved in DMF (5 ml). Add NaN3(0,065 g, 1.0 mmol), the mixture is heated to 60°C and stirred for 3 hours. The reaction mixture is cooled to room temperature and add water. Extracted with ethyl acetate and the organic layer was washed with a saturated solution of salt. The organic layer is dried over sodium sulfate, filtered and concentrated on a rotary evaporator. Additionally dried under a strong vacuum. Get 0,100 g of methyl ester of 4-{2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}-2-isopropoxybenzoic acid with a yield of 94%.

Step 7: To a solution of azide from stage 6 (0,100 g, 0.16 mmol) in THF (2 ml) add Ph3P (polymeric carrier: 3 mmol Ph3P/gram) (0,100 g, 0.30 mmol). The reaction mixture was stirred at room temperature for 24 hours. Then add water (0.5 ml) and the reaction mixture was stirred at room temperature overnight. The reaction solution is filtered and the filtrate concentrated on a rotary evaporator. The resulting residue is purified on silikagelevye preparative plates using 2% MeOH in dichloromethane as eluent. Get 0,020 g of methyl ester of 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}-2-isopropoxybenzoic acid with a yield of 21%.

Step 8: To a solution of amine from stage 7 (0,020 is, 0,034 mmol) and [(3,4-dichlorophenyl)methyl]sulphonylchloride (0.015 g, 0,058 mmol) in dichloromethane (2 ml) is added aqueous saturated solution of Na2CO3(2 ml). The reaction mixture was stirred at room temperature for two hours. Then the reaction solution is separated, the organic phase is collected, washed with saturated salt solution and dried over sodium sulfate. The organic solution is filtered and concentrated on a rotary evaporator. The resulting residue is purified on silikagelevye preparative plates using 2% MeOH in dichloromethane as eluent. Get to 0.022 g of the desired sulfonamida (white solid) with a yield of 79%. m/z (M+1) 821.

Step 9: To a solution of ester from stage 8 (0,022 g, or 0.027 mmol) in a mixture of THF (1 ml) and MeOH (1 ml) was added 1 N. NaOH (1 ml). The reaction mixture was stirred at room temperature for 5 days. THF and MeOH is removed on a rotary evaporator. Extracted with dichloromethane, separated and collect the aqueous layer. The water layer is neutralized 1 N. HCl and collect the resulting precipitate. Get 0,021 g indicated in the title acid (solid yellow substance) with the release of 96%. m/z (M-1) 805.

Analysis of the activity

Coumarin analysis

7-hydroxycoumarin-6-heptenoic used as Monomeric substrate for cPLA2as previously reported (Huang, Z. et al., 1994, Analytical Biochemistry 222, 110-115). inhibitory mixed with 200 µl of sample buffer (80 mm Heped, pH 7.5, 1 mm EDTA)containing 60 μm 7-hydroxycoumarin-6-heptanoate. The reaction is initiated by adding 4 μg of cPLA250 μl of sample buffer. Hydrolysis of ester 7-hydroxycoumarin-6-heptanoate control fluorometers, conducting excitation at 360 nm and measuring emission at 460 nm. The enzyme activity is proportional to the increase in emission at 460 nm per minute. In the presence of inhibitor cPLA2the rate of increase is less.

Example #Coumarin

IC50(µm)
Example 10,42
Example 22
Example 32,5
Example 456
Example 53
Example 62,0
Example 70,55
Example 82
Example 90,7
Example 100,57
Example 110,45
Example 12150
Example 130,64
Example 140,8
Example 150,63
Example 160,98
Example 170,2
Example 18 0,4
Example 190,31
Example 201,1
Example 211,1
Example 221,8
Example 231,5
Example 240,34
Example 253,4
Example 261,1
Example 270,8
Example 280,95
Example 290,19
Example 300,15
Example 310,15
Example 320,085
Example 332,9
Example 350,33
Example 360,5
Example 370,37
Example 380,5
Example 390,32
Example 400,73
Example 410,2
Example 420,18
Example 430,2
Example 440,25
Example 45the 4.7
Example 464,8
Example 470,58
Example 482,35
Example 491,1
Example 500,69
Example 512,2
Example 520,13
Example 530,37
Example 540,31
Example 550,26
Example 560,13
Example 570,28
Example 580,36
Example 590,29
Example 600,15
Example 610,34
Example 620,38
Example 630,30
Example 640,12
Example 650,13
Example 660,15
Example 670,14
Example 680,16
Example 690,15
Example 700,18
Example 710,45
Example 720,28
Example 730,30
Example 740,28
Example 750,4
Example 760,4
Example 770,48
Example 78 0,34
Example 790,15
Example 803,7
Example 810,47
Example 820,5
Example 830,45
Example 840,5
Example 850,4
Example 860,6
Example 871,2
Example 88<7,4
Example 890,38
Example 900,65
Example 910,5
Example 921,0
Example 930,56
Example 940,8
Example 950,85
Example 960,95
Example 970,95
Example 981,1
Example 991,0
Example 1000,12
Example 1010,1
Example 1020,19
Example 1031,1
Example 1041,1
Example 1050,65
Example 1060,22
Example 1070,33
Example 1080,15
Example 1090,4
Example 1100,5
Example 1111,0
Example 1121,2
Example 1131,3
Example 1141,1
Example 1150,9
Example 1161,2
Example 1171,6
Example 1180,4
Example 1190,4
Example 1200,4
Example 1210,46
Example 1222,5
Example 1231,5
Example 1240,8
Example 1251,4
Example 1260,2
Example 1270,2
Example 1280,32
Example 1290,13
Example 1300,17
Example 1310,2
Example 1320,2
Example 1330,09
Example 134>1
Example 1350,2
Example 1360,18
Example 37 not defined
Example 1380,2
Example 1391,7
Example 1400,2
Example 1410,17
Example 142not defined
Example 143not defined
Example 144not defined
Example 145not defined
Example 146not defined
Example 147not defined
Example 148not defined
Example 149not defined
Example 150not defined
Example 151not defined
Example 1520,32
Example 1530,16
Example 1540,35
Example 1550,45
Example 1560,16
Example 1570,2
Example 1580,2
Example 1590,65
Example 1600,19
Example 1610,32
Example 1621,0
Example 163 0,3
Example 1640,2
Example 1650,53
Example 1660,4
Example 1670,19
Example 1680,27
Example 1690,46
Example 1700,95
Example 1710,36
Example 1720,35
Example 1730,4
Example 1741,1
Example 1750,37
Example 1760,4
Example 1770,9
Example 1780,65
Example 1790,9
Example 1800,23
Example 1810,32
Example 1820,6
Example 1830,17
Example 1840,35
Example 1850,17
Example 1860,1
Example 1870,2
Example 188not defined
Example 189not defined
Example 1900,53
Example 1910,2
Por the measures 192 <3,7
Example 1931,8
Example 1941
Example 1951
Example 1960,56
Example 1970,4
Example 1980,7
Example 1990,45
Example 2000,35
Example 2010,35
Example 2020,3
Example 2030,69
Example 2040,2
Example 2050,37
Example 2060,5
Example 2071,4
Example 2080,24
Example 2090,35
Example 2100,15
Example 2110,4
Example 2120,18
Example 2130,45
Example 214not defined
Example 215not defined
Example 216not defined
Example 2172,6
Example 2180,14
Example 2190,4
Example 2200,4
Example 2210,5
Example 2220,19
Example 2230,6
Example 2240,25
Example 2250,4
Example 2260,14
Example 2270,16
Example 2280,4
Example 2290,5
Example 2300,15
Example 2310,25
Example 2320,13
Example 2330,34
Example 2340,23
Example 2350,18
Example 2360,085
Example 2370,2
Example 2380,25
Example 2390,48
Example 2400,32
Example 2410,54
Example 2421,3
Example 2430,75
Example 2441,3
Example 2450,9
Example 2461,2
Example 2471,2
Example 2481,2
Example 2490,67
Example 2502,1
Example 2511,5
Example 2520,73
Example 2530,75
Example 2540,26
Example 2550,5
Example 2560,6
Example 2570,5
Example 2580,8
Example 2590,2
Example 2600,37
Example 2610,25
Example 2620,53
Example 2630,32
Example 2640,4
Example 2650,37
Example 2660,16
Example 2670,074
Example 2680,09
Example 2690,15
Example 2700,14
Example 2710,15
Example 2720,1
Example 2730,11
Example 274not defined
Example 2750,24
Example 2760,32
Example 2770,6
Example 2781,9
Example 2790,16
Example 2800,35
Example 281not defined
Example 282not defined
Example 2830,5
Example 2840,4
Example 285not defined
Example 286not defined
Example 2870,42
Example 2880,4
Example 2890,9
Example 290not defined
Example 291not defined
Example 292not defined
Example 293not defined
Example 294not defined
Example 2950,55
Example 2960,32
Example 2970,3
Example 2980,19
Example 2991,0
Example 300>2

Compounds of the invention inhibit the activity of cPLA2required for delivery of the substrate arachidonic acid for cyclooxygenase-1 or -2 and 5-lipoxygenase, which, in turn, iniciar what are the production of prostaglandins and leukotrienes, respectively. In addition, the activity of cPLA2is important for the production of lysophospholipid, which is a precursor of PAF. Thus, the data connection is applicable for the treatment and prevention of pathological conditions that include leukotrienes, prostaglandins or PAF. Moreover, in cases in which play the role of more than one of these agents, an inhibitor of cPLA2as expected, is more effective than receptor antagonists leukotriene, prostaglandin, or PAF, as well as more effective than inhibitors of cyclooxygenase or 5-lipoxygenase.

Therefore, compounds, pharmaceutical compositions and modes of the present invention is applicable for the treatment and prevention of disorders that can be treated with inhibitors of cyclooxygenase-2, cyclooxygenase-1 and 5-lipoxygenase, as well as PAF receptor antagonists, leukotriene or prostaglandin. Diseases that can be treated by the compounds of the present invention, include, but are not limited to, pulmonary disorders including diseases such as asthma, chronic bronchitis, and related obstructive airway disease; allergies and allergic reactions such as allergic rhinitis, contact dermatitis, allergic conjunctivitis and similar; inflammation, such as arthritis or inflammatory disease is Chechnya; skin disorders such as psoriasis, atopic eczema, acne, damage by ultraviolet light, burns and dermatitis; cardiovascular diseases such as atherosclerosis, angina, myocardial ischemia, hypertension, platelet aggregation and similar; and renal failure caused by immunological or chemical. Drugs can also be chitosamine, preventing damage to the mucous membranes of the gastro-intestinal tract harmful factors. Connections will be applicable for the treatment of respiratory distress syndrome in adults, endotoxic shock and injury caused by ischemia including myocardial injury or brain injury.

Methods of treating, suppressing, alleviate or ameliorate asthma in this invention include methods of treating acquired bronchial asthma (also known as allergic asthma or atopic asthma), hereditary asthma (also known as non-allergic asthma or Autopista asthma) or their combinations, which are called mixed asthma. Condition of patients experiencing or exposed to acquired or allergic asthma include cases caused by or associated with many allergens, such as pollen, spores, grass or weeds, pet dander, dust, mites, etc. Wid is also what allergens and other irritants by themselves are present at various points during the year, these types of cases also called seasonal asthma. The group acquired asthma also includes an bronchial asthma and allergic aspergillosis of the bronchi and lungs.

Hereditary asthma, which can be treated or to facilitate these methods include cases caused by infectious agents, such as those that cause colds and flu in adults and respiratory syncytial virus (RSV), rhinovirus and influenza virus, common in children. Also included asthmatic condition that can be caused by some asthmatics exercise and/or cold air. The methods are applicable for the treatment of hereditary asthma associated with industrial or professional effects such as smog, ozone, harmful gases, sulfur dioxide, nitrogen oxides, fumes, including isocyanates, evaporation paints, plastics, polyurethanes, varnishes, etc., wood, vegetable dust or other organic dust, etc. Methods are also applicable for asthma cases associated with food additives, preservatives and drugs. Normal substances data types include food dyes such as tartrazine, preservatives, similar to bisulfite and metabisulfite is, and pharmacological agents, such as aspirin and nonsteroidal anti-inflammatory drugs (NSAID). Also included are methods of treating, suppressing or alleviating types of asthma, called hidden asthma or cough variant asthma.

The described methods are also applicable for the treatment or relief of hereditary asthma associated with gastroesophageal reflux (GERD), which can stimulate bronchostenosis. GERD, together with retained secretions of the body, suppress cough and exposure to allergens and irritants in the bedroom, can contribute to the asthmatic condition called nocturnal asthma or Noctumal asthma. Ways to treat, suppress or alleviate asthma associated with GERD, pharmaceutically effective amount of the compounds of this invention can be used, as described here, in combination with a pharmaceutically effective amount of drug for the treatment of GERD. These drugs include, but are not limited to, proton pump inhibitor similar to tablets pantoprazole sodium delayed-action brand PROTONIX®the capsules of omeprazole delayed-action brand PRILOSEC®, tablets rabeprazole sodium delayed-action brand ACIPHEX®or capsules lansoprazole slow Astia brand PREVACID ®.

These compounds are particularly suitable for the treatment of arthritic and/or rheumatic disorders, including, but not limited to, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and disease Steele. Compounds according to this invention will be applicable for the treatment of postoperative inflammation, including inflammation after ophthalmic surgery such as cataract surgery or refractive surgery.

Compounds according to this invention can be used as febrifuge. Compounds according to this invention can be used in the treatment of pain, particularly pain associated with inflammation. Specific methods include, but are not limited to, methods of treating Central pain, peripheral pain, musculoskeletal pain, lumbosacral pain, pain associated with damage to structural or soft tissue, pain associated with progressive diseases such as cancer and degenerative diseases, neuropathic pain, which may include severe pain, such as acute injury or trauma, pre - and post-operative pain, pain due to migraine, toothache, etc., chronic pain such as neuropathic diabetic status PE is everynoe neuropathy, post-herpetic neuralgia, fibromyalgia, and inflammatory conditions such as osteoarthritis and rheumatoid arthritis, due to acute injury or trauma, and pain associated with carcinoma.

Further, the invention provides a way of relief, suppression, reduction or treatment of arthritic and rheumatic disorders in a mammal, the method comprises administration to a mammal in need of this pharmaceutically effective amount of a chemical inhibitor of the enzyme phospholipase, especially enzymes phospholipase A2as defined in the present description, and pharmaceutically-effective amount of anti-rheumatic drug.

Combinations for the treatment of arthritic and rheumatic disorders may include, but are not limited to, commercially available anti-rheumatic drugs, such as naproxen, which is sold in the form of tablets delayed action ECNAPROSYN®, tablets NAPROSYN®, ANAPROX®and ANAPROX®DS and NAPROSYN suspension®Roche Labs, tablets celecoxib brand CELEBREX®, rofecoksib brand VIOXX®, betamethasone brand CELESTONE®capsules penitsillamin brand CUPRAMINE®, tablet penitsillamin brand DEPEN®suspense the injection methylprednisolone acetate DEPOMEDROL, tablets Leflunomide brand ARAVA™, tablet sulfasalazine delayed action brand AZULFIDIINE EN-tabs®, capsules piroxicam brand FELDENE®tablets, diclofenac potassium CATAFLAM®tablets of diclofenac sodium delayed-action VOLTAREN®tablets of diclofenac sodium prolonged action VOLTAREN®XR products etanercept ENBREL®other commercially available anti-rheumatic drugs.

Also applicable are capsules cyclosporine brand GENGRAF™products sirolimus brand RAPAMUNE®capsules or oral solution cyclosporine brand NEORAL®, tablet or IV injection of azathioprine brand IMURAN®capsules, oral suspension and suppositories brand INDOCIN®oral solution prednisolone sodium phosphate PEDIAPED®sulphate hydroxychloride brand PLAQUENIL®syrup prednisolone PRELONE brand®the recombinant infliximab for IV injection REMICADE®and methylprednisolone sodium succinate for injection SOLU-MEDROL®.

Also applicable in the combinations according to this invention are compounds of gold and products applicable for the treatment of arthritis and rheumatic conditions, such as auranofin or and Yecla of thiomalate gold sodium MYOCHRISYINE ®.

Each of these products, you can enter a pharmaceutically effective doses and application methods known from the prior art, such as described for the products in the Physicians' Desk Reference, 55 Edition, 2001, Medical Economics Co., Inc., Montvale, N.J.

Compounds according to this invention can also be entered by the methods according to this invention with analgesic and anti-inflammatory drugs such as NSAIDs (NSAID), aspirin and other salicylates. Examples of applicable drugs include ibuprofen (MOTRIN®, ADVIL®), naproxen (NAPROSYN®), sulindac (CLINORIL®), diclofenac (VOLTAREN®), piroxicam (FELDENE®), Ketoprofen (ORUDIS®), diflunisal (DOLOBID®), nabumetone (RELAFEN®), etodolac (LODINE®), oxaprozin (DAYPRO®), indomethacin (INDOCIN®), melicocca (MOBICOX®), valdecoxib and enterococci. Aspirin is an anti-inflammatory drug, when given in high doses, otherwise it is a pain reliever, like acetaminophen (TYLENOL®).

Suitable inhibitors of cyclooxygenase 2 (COX-2) for use with methods according to this invention include, but are not limited to, 2-(4-ethoxyphenyl)-3-(4-methanesulfonyl)pyrazolo[1,5-b]pyridazin, CDC-501, celecoxib, COX-189, 4-(2-oxo-3-phenyl-2,3-dihydrooxazolo-4-yl)bensalah named, CS-179 CS-502, D-1367, darbufelone, DFP, DRF-marketed 4 367, flosulide, JTE-522 (4-(4-cyclohexyl-2-methyl-5-oxazolyl)-2-forbindelsesfaneblad), L-745337, L-768277, L-776967, L-783003, L-791456, L-804600, meloxicam, MK663 (etoricoxib), nimesulide, NS-398, parecoxib, 1-methylsulphonyl-4-(1,1-dimethyl-4-(4-forfinal)cyclopent-2,4-Dien-3-yl)benzene, 4-(1,5-dihydro-6-fluoro-7-methoxy-3-(trifluoromethyl)-(2)-benzothiophen about(4,3-C)pyrazole-1-yl)benzosulfimide, 4,4-dimethyl-2-phenyl-3-(4-methylsulphonyl)phenyl)CYCLOBUTANE, 4-amino-N-(4-(2-fluoro-5-trifluoromethyl-thiazol-2-yl)benzosulfimide, 1-(7-tert-butyl-2,3-dihydro-3,3-dimethyl-5-benzofuranyl)-4-cyclopropylmethyl-1-he, Pharmaprojects No. 6089 (Kotobuki Pharmaceutical), RS-113472, RWJ-63556, S-2474, S-33516, SC-299, SC-5755, valdecoxib, UR-8877, UR-8813, UR-8880. Further suitable COX-2 inhibitors for use according to the invention include parecoxib, MK, 4-(4-cyclohexyl-2-methyl-5-oxazolyl)-2-forbindelsesfaneblad (JTE-522), nimesulid, flosulide, DFP and 2-(4-ethoxyphenyl)-3-(4-methanesulfonyl)pyrazolo[1,5-b]pyridazin and their physiologically acceptable salt, ester or solvate.

Such compositions are also applicable in the treatment of menstrual cramps, preterm birth, tendonitis, bursitis, allergic neuritis, cytomegalovirus infection, apoptosis including HIV-induced apoptosis, lumbago, liver disease including hepatitis.

These methods are also applicable for the treatment of gastrointestinal conditions such as Pospolita the data bowel disease, Crohn's disease, gastritis, symptoms of inflamed intestines and ulcerative colitis and for the prevention or treatment of cancer, such as colon cancer. Compounds and compositions of the present invention is also applicable for the prevention or treatment of benign and malignant tumors/neoplasia including cancer, such as colorectal cancer, brain cancer, bone cancer, neoplasia of epithelial cells (epithelial carcinoma)such as carcinoma, basal cell adenocarcinoma, cancer of the gastrointestinal tract, including cancer of the lip, oral cancer, esophageal cancer, cancer of the small intestine and stomach cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer breast and skin cancer, such as carcinoma, squamous cell cancer and basal cell cancer, prostate cancer, renal cell carcinoma, and other known cancers that affect epithelial cells throughout the body. It is expected that the compositions of the present invention is particularly suitable for these types of neoplasia, cancer of the gastrointestinal tract, Barret's esophagus, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, cervical cancer, lung cancer, breast cancer and skin cancer, such as carcinoma, squamous cell cancer and basal cells. Compounds and methods according to this invention can also what to use for the treatment of fibrosis, caused by radiation therapy. Such compositions can be used for the treatment of patients with adenomatous polyps, including patients with familial adenomatous polyps (FAP). In addition, such compositions can be used for preventing the formation of polyps in patients with risk of FAP. Compounds according to this invention is applicable for the treatment of cancer due to its antiangiogenic action.

Further uses include the treatment of inflammation in such diseases as vascular diseases, headaches and migraines, Nowotny panarteritis, strumitis, aplastic anemia, Hodgkin's disease, scleroderma, rheumatism, diabetes type I, neuromuscular disorders, including bulbospinal paralysis, disease of the white matter, including multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet, polymyositis, gingivitis, nephritis, allergic reactions, swelling caused by injury including brain edema, myocardial ischemia and similar. Also includes the treatment of ophthalmic diseases such as retinitis, conjunctivitis, retinopathy, uveitis, photophobia, and of acute injury to the eye tissue. Also included treatment of pneumonia and inflammation of the upper respiratory tract, such as inflammation associated with viral infections and cystic fibrosis, and bone resorption, such accoucheuse osteoporosis. These compounds and compositions are applicable for the treatment of certain diseases of the nervous system, such as cortical dementia, including Alzheimer's disease, neurodegeneration and injury to the Central nervous system as a result of stroke, ischemia or trauma. Compounds according to this invention may also be applicable in the treatment of Parkinson's disease.

Treatment of pain include the administration to a mammal suffering from such pain, pharmaceutically effective amounts of compounds according to this invention, one or in combination with one or more additional pharmaceutically effective agents for the treatment of pain or inflammation or related with medical perspective conditions. Examples of drugs that can be combined with the present compounds are analgesics, antiangiogenic drugs, antineoplastics drugs. These compounds can also be combined with antiepileptic compounds that possess analgesic properties, such as gabapentin, pregabalin.

One such fluid method according to the present invention includes the administration to a mammal, if necessary, pharmaceutically effective amounts of compounds according to this invention and a pharmaceutically effective amount of a non-toxic ant is honest receptor N-methyl-D-aspartate (NMDA) and/or agent, which blocks at least one of the major intracellular sequences of activation of the NMDA receptor. Examples of antagonists of the NMDA receptor, applicable in these methods include dextromethorphan, dextrorphan, amantadine and memantine, or their pharmaceutically acceptable salts.

Another method of treatment of inflammation and inflammatory diseases include co-administration to a mammal, when necessary, an inhibitor of inducible synthase nitric oxide compound according to this invention. This combination is applicable for prophylactic or therapeutic use in a mammal experiencing or subject to abnormally low levels of activity synthase nitric oxide (NOS), in particular suffering from high blood pressure or an increased risk of pulmonary hypertension, ischemic stroke, myocardial infarction, heart failure, progressive renal disease, thrombosis, reperfusion injury or degenerative nervous system disorders such as Alzheimer's disease, or chronically experiencing a state of hypoxia.

Methods according to this invention also include methods of treating or preventing neoplasia in a mammal, including man, in need of such treatment or prevention. The method comprises treating the mammal therapist who Cesky effective amount of the compounds of this invention in combination with an inhibitor of MMP. These two components can be further optionally combined with one or more agents selected from the antiangiogenic drug, antineoplastic means, excipients, immunotherapy, analgesic and/or radiotherapeutic agents. One such multi-component therapy involves the administration to a mammal, if necessary, the compounds according to this invention, the inhibitor of metalloproteinases matrix and antineoplastics tools.

The methods and combinations of this invention can be used for the treatment and prevention of neoplasia, including gralow lentiginous melanoma, actinic keratoses, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenocarcinoma, adenocarcinoma, astrocytic tumor, carcinoma of bartolemeu cancer, carcinoma, basal cell carcinoma bronchial cancer, capillary argentaffin, carcinoma, carcinosarcoma, cavernous cholangiocarcinoma, cartilage sarcoma, papiloma/carcinoma holodnogo plexus carcinoma clear, cystadenoma, endodermal tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometroid adenocarcinoma, the ependymal glioma, epithelioid cell sarcoma, abnormal Ewing sarcoma, fibrous education, focal nodular gipec the Asia, gastrinoma, germ cell tumors, glioblastoma, glucagonoma, hemangioblastoma, hemangioendothelioma, hemangioma, adenoma of the liver, hepatic adenomatosis, hepatocellular carcinoma, a tumor of the beta cells, intraepithelial a neoplasia, a neoplasia squamous cells, invasive squamous cell carcinoma, both carcinoma, leiomyosarcoma, malignant lentigo-melanoma, malignant melanoma, malignant tumors mesothelia, medulloblastoma, medulloepithelioma, melanoma, meningeal, mesothelial, metastatic carcinoma, mucoepidermoid carcinoma, neuroblastoma, neuroepithelial adenocarcinoma, nodular melanoma, oat cell carcinoma, oligodendroglioma, osteosarcoma, pancreatic polypeptide, papillary serous adenocarcinoma, the tumor cells of the pineal gland, pituitary tumor, plasmacytoma, pseudosarcoma, pulmonary blastoma, renal cell cancer, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, small cell carcinoma, carcinoma of the soft tissues, the tumor secreting somatostatin, squamous carcinoma, squamous carcinoma cells, surface scattering melanoma, undifferentiated carcinoma, uveal melanoma, warty cancer, vipoma, well differentiated carcinoma, and Wilm tumor.

Antineoplastic is the means, applicable in the described combination therapies include anastrozole, calcium carbonate, capecitabine, carboplatin, cisplatin, Cell Pathways CP-461, docetaxel, doxorubicin, etoposide, fluorouracil, fluoxymesterone, gemcitabine, goserelin, irinotecan, ketoconazole, letrozole, leucovorin, levamisole, megestrol, mitoxantrone, paclitaxel, raloxifene, retinoic acid, tamoxifen, titera, topotecan, toremifene, vinorelbine, vinblastine, vincristine, selenium (Selenomethionine), ursodeoxycholic acid, sulindac sulfon, exemestane and eflornithine (DFMO), 1-[4-(2-azepin-1 ylethoxy)benzyl]-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol (also known as TSE-424) and 2-(4-hydroxyphenyl)-3-methyl-1-(4-(2-piperidine-1-ylethoxy)benzyl]-1H-indol-5-ol (also known as ERA-923).

The invention also includes methods of using the described compounds in combination with the protein inhibitor of interleukin-1, such as an antagonist of IL-1 receptor (IL-Ira) for the prevention or treatment of inflammatory diseases in mammals. Acute and chronic inflammatory diseases, in which the mediator is interleukin-1 (IL-1) and treatment which are of interest in these methods include, but are not limited to, acute pancreatitis; ALS; Alzheimer's disease; cachexia/anorexia; asthma; atherosclerosis; chronic fatigue syndrome, fever is; diabetes (e.g., insulin diabetes); glomerulonephritis; graft rejection; hemorrhagic shock; hyperalgesia, inflammatory bowel disease; inflammatory condition of the joints, including osteoarthritis, psoriatic arthritis and rheumatoid arthritis; ischemic injury, including cerebral ischemia (e.g., traumatic brain injury as a result of trauma, epilepsy, hemorrhage or stroke, which may lead to neurodegeneration); lung diseases (e.g., ARDS); multiple myeloma; multiple sclerosis; myelogenous (e.g., AML and CML) and other leukemias; myopathies (e.g., muscle protein metabolism, especially in sepsis); osteoporosis; Parkinson's disease; pain; premature labor; psoriasis; reperfusion injury; septic shock; side effects from radiation therapy, disease of the temporomandibular joint, tumor metastasis; or an inflammatory condition resulting strain, sprain, cartilage damage, trauma, orthopedic surgery, infection or other pathological processes.

This invention also provides a method of introducing one or more compounds of the present invention a woman, when necessary, to essentially prevent or reduce changes in the female reproductive system associated with the beginning or continuation of b is of pregnancy. Also offers substantial prevention or reduction of uterine contractions that occur during pregnancy or related menorrhagia. These methods can optionally include co-administration of compounds according to this invention with progesterone, progestin or gestagenna tool.

Each of the methods according to this invention includes the introduction of a mammal in need of such treatment, a pharmaceutically or therapeutically effective amount of the compounds according to the invention. In the examples described here combinational therapies need to understand that the introduction of further includes a pharmaceutically or therapeutically effective amount of a second pharmaceutical product in question. The second or further described here pharmacological drug may be injected doses and regimens known in the prior art.

Compounds according to this invention can also be used in comparable veterinary treatments, particularly for veterinary treatment, suppression or attenuation of inflammation and pain. It is clear that these methods are of particular interest to animal companions such as dogs and cats, and for use in the treatment of agricultural mammals, such as cattle, horses and, mules, donkeys, goats, pigs, sheep, etc. these methods can be used to treat types of inflammation and pain, which are known in veterinary medicine, including, but not limited to, pain and inflammation associated with arthritis, defective joints, defects of the joints, such as hip dysplasia, tendonitis, inflammation of the ligaments, inflammation of the hoof, solid tumor on the leg of a horse and bursitis, or pain and inflammation associated with surgery, accident, injury or disease, such as illness Lima. These compounds can also be used in the treatment of airway inflammation, such as status asthma, laryngitis, tracheitis, bronchitis, rhinitis or pharyngitis.

Compounds according to this invention can also be used in comparable veterinary treatments, particularly for veterinary treatment, suppression or attenuation of inflammation and pain associated with asthmatic conditions. It is clear that these methods are of particular interest to animal companions such as dogs and cats, especially suffering from feline asthma. These compounds can also be used in the treatment of airway inflammation, such as status asthma, laryngitis, tracheitis, bronchitis, rhinitis and pharyngitis.

Compounds according to this invention can be used is W ith in the veterinary treatment of asthma and asthmatic conditions in combination with other methods of treatment of asthma, such as feline asthma, including oral or injectable steroids, cyproheptadine at, cyclosporine a or antibodies antiinterleukin-5.

Each of these veterinary ways includes an introduction to the mammal, if necessary, pharmaceutically effective amounts of compounds of this invention or its pharmaceutically acceptable salt forms. Compounds according to this invention can be used for the treatment of humans or animals together with other medicines or food additives known from the prior art for treating, suppressing or alleviating inflammation or pain. These may include aspirin (including buffered aspirin, aspirin with Maalox and aspirin, covered intersolubility shell), COX-2 inhibitors such as celecoxib, deatsetilirovanie carboxylic acids, such as magnesium salicylate, salicylamide or sodium salicylate, acetic acid, such as diclofenac and etodolac, propionic acids such as ibuprofen, naproxen (available in the form of trading stamps NAPROSYN®and EQUIPROXEN®), Ketoprofen, RIMADYL®(carprofen), flunixin, meglumine, fanmovie acid, such as telenova acid, meganova acid, meclofenamic acid (ARQUEL®or niflumova acid, enol acid, such as oxyphenbutazone, phenylbutazone, PIR is xicam or dieron, or non-acidic compounds, similar to nabumetone. Also in veterinary use dimethyl sulfoxide (DMSO), orgotein (such as orgotein brand PALOSEIN®), polysulfonamide glycosaminoglycans or PS-GAG (such as polysulfonyl of glycosaminoglycan brand ADEQUAN®), hyaluronic acid and its natural and synthetic analogues, Ketorolac, tromethamine (such as brand TORADOL®), FELDENE®(piroxicam) or METACAM®(meloxicam).

Nutritional supplements used for the treatment of humans and animals include glucosamine, chondroitin sulfate, MSM and omega-3 fatty acids and other fats from cold water fish. Compounds and methods according to this invention can also be used together with physical therapy, massage, chiropractic nowadays and acupuncture humans and animals. Every drug and every dietary Supplement you can enter a mammal in question, using modes and effective dosages, well-known from the prior art.

1. The compound of the formula

where R is -(CH2)n-And where And

;

where each of b and C independently represents phenyl or phenyl substituted by 1-3 substituents, independently selected Shalagina, -CN, -Cho, -CF3, -OCF3, -OH, -C1-C6of alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl), and-NO2; or

n is an integer from 0 to 3;

n1an integer from 1 to 3;

n2an integer from 0 to 4;

n3an integer from 0 to 3;

n4an integer from 0 to 2;

X1selected from a chemical bond, -S-, -S(O)2-, -NH-, -NHC(O)- and-C=C-,

R1selected from C1-C6of alkyl, C1-C6foralkyl, C3-C6cycloalkyl, tetrahydropyranyl, CN, -M(C1-C6alkyl)2, phenyl, pyridinyl, pyrimidinyl, furil, teinila, naphthyl, morpholinyl, triazolyl, pyrazolyl, piperidinyl, pyrrolidinyl, imidazolyl, piperidinyl, thiazolidine, thiomorpholine, tetrazolyl, benzoxazolyl, imidazolidin-2-tonila, 7,7-dimethylbicyclo[2.2.1]heptane-2-onila, benzo[1,2 .5]oxadiazolyl, 2-oxa-5-azabicyclo[2.2.1]heptyl and pyrrolyl, each of which is optionally substituted by 1-3 substituents, independently selected from halogen, -CN, -Cho, -CF3, OCF3, -OH, -C1-C6of alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -NO2, -SO2(C1-C3alkyl), -SO 2NH2, -SO2N(C1-C3alkyl)2, -COOH, -CH2-COOH, pyridyl, 2-methylthiazolyl, morpholino, 1-chloro-2-methylpropyl, phenyl (optionally optionally substituted by one or more Halogens), benzyloxy and

;

X2selected from-O-, -CH2-, -S-, -SO-, -SO2-, -NH -, and

,

R2represents a ring group selected from phenyl and thienyl groups, and the ring group substituted by a group of the formula -(CH2)n4-CO2N; and, in addition, optionally substituted by 1 or 2 additional substituents independently selected from halogen, -C1-C6the alkyl and-C1-C6alkoxy;

R3selected from H, halogen and-NO2;

R4selected from H, halogen, morpholino;

or its pharmaceutically acceptable salt form.

2. The compound according to claim 1, where n is equal to 0.

3. The compound according to claim 1 or 2, where a represents a group

.

4. The compound according to claim 1 or 2, where R3is halogen.

5. The compound according to claim 1 or 2, where R4selected from halogen or morpholino.

6. The compound according to claim 1 or 2, where R3and R4are 5 and 6 the provisions of the indole ring.

7. The compound according to claim 1 or 2, where n3equal to 1

8. The compound according to claim 1 or 2, where X2represents OH, -SO2-, -NH - or-CH2-.

9. The compound according to claim 1 or 2, where R2represents a group selected from the

;;;

where n4is 0-2;

R8and R9independently selected from H, halogen, -C1-C6the alkyl and C1-C6alkoxy.

10. The compound according to claim 1 or 2, where n40.

11. The connection according to claim 9, where -(CH2)n4-CO2N is in position 4 of the phenyl ring.

12. The compound according to claim 1 or 2, where n1is 1 or 2.

13. The compound according to claim 1 or 2, where n2is 0, 1 or 2.

14. The compound according to claim 1 or 2, where n1and n2both equal to 1.

15. The compound according to claim 1 or 2, where X1selected from a chemical bond, -S - and-NH-.

16. The compound according to claim 1 or 2, where R1selected from C1-C6of alkyl, C3-C6cycloalkyl, phenyl, pyridinyl, naphthyl, tetrazolyl, each of which is optionally substituted by 1-3 substituents, independently selected from halogen, -CN, -Cho, -CF3, OCF3, -OH, -C1-C6of alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -NO2, -SO2(C1-C3alkyl), -SO2NH2, -SO2N(C1-the 3alkyl)2, -COOH, -CH2-COOH, phenyl (optionally optionally substituted by one or more halogen and benzyloxy.

17. The compound according to claim 1 or 2, where R1has the formula

where R5, R6and R6' are independently selected from H, halogen, -CN, -Cho, -CF3, OCF3, -OH, -C1-C6of alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), and-NO2.

18. The compound according to claim 1, having the formula (II) or (III)

or

19. Connection p, where n3=1.

20. Connection p or 19, where R2represents phenyl substituted by a group of the formula -(CH2)n4-CO2N, and optionally substituted 1 or 2 additional substituents independently selected from halogen, -C1-C6the alkyl and C1-C6alkoxy.

21. The compound according to claim 1, having the formula (IV) or (V)

or

where n1an integer from 1 to 3;

n3an integer from 1 to 3;

R5, R6and R6' are independently selected from H, halogen, -CN, -Cho, -CF3-HE , C1-C6of alkyl, C 1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), and-NO2;

X1selected from a chemical bond, -S - and-NH-;

X2selected from-O-, -SO2- and-CH2-;

R2represents a group selected from the

;;

or;

R8and R9independently selected from H, halogen, -C1-C6the alkyl and C1-C6alkoxy;

n4an integer from 0 to 2;

R3selected from H or halogen; and

R4selected from H, halogen, morpholino.

22. The compound according to claim 1, having the formula (VI) or (VII)

where X1selected from a chemical bond, -S - and-NH-;

X2selected from-O-, -SO2- and-CH2-;

R3selected from H or halogen; and

R4selected from H, halogen, morpholino;

n1an integer from 1 to 2;

n2an integer from 1 to 2;

R5, R6and R6' are independently selected from H, halogen, -CN, -Cho, -CF3, OCF3, -OH, -C1-C6of alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C 6alkyl), and-NO2;

R8and R9independently selected from H, halogen, C1-C6the alkyl and C1-C6alkoxy.

23. Connection on p.22 of the formula (VI) or (VII), where

n1equal to 1 and n2is 1.

24. The compound according to claim 1 or 2, where X1represents a chemical bond.

25. The compound according to claim 1, which is selected from the group consisting of

4-[2-(1-benzhydryl-2-{2-[(benzylmethyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoic acid;

4-[2-(1-benzhydryl-5-chloro-2-{2-[(isopropylphenyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid;

4-[2-(1-benzhydryl-2-{2-[(butylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(1-methyl-1H-imidazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-2-(2-{[(5-bromo-6-chloro-3-pyridinyl)sulfonyl]amino}ethyl)-5-chloro-1H-indol-3-yl]ethoxy)benzoic acid;

4-[2-(1-benzhydryl-5-chloro-2-{2-[({[(1R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy] benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-({[(methylsulphonyl)methyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-({[(2-(1-naphthyl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-{2-[1-enshell-5-chloro-2-{2-[({2-nitrobenzyl}sulfonyl)amino]ethyl}-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,5-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-({[(3-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-({[(4-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(4-terbisil)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(4-chlorbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[2-(2-{[(2-aminobenzyl)sulfonyl]amino}ethyl)-5-chloro-1-(diphenylmethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(dimethylamino)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-diferensial)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-naphthylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

3-({[(2-{1-benzhydryl-3-[2-(4-carboxyphenoxy)ethyl]-5-chloro-1H-indol-2-yl}ethyl)amino]sulfonyl}methyl)benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-({[(E)-2-phenylethenyl]sulfone the}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(trifluoromethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-[2-(1-benzhydryl-5-chloro-2-{2-[(cyclopropylmethyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid;

4-(2-{1-benzhydryl-2-[2-({[3,5-bis(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-5-chloro-1H-indol-3-yl}ethoxy)benzoic acid;

2-{[(2-{1-benzhydryl-3-[2-(4-carboxyphenoxy)ethyl]-5-chloro-1H-indol-2-yl}ethyl)amino]sulfonyl}benzoic acid;

4-[2-(1-benzhydryl-5-chloro-2-{2-[(2-naphthylmethyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,5-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,3-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid; and

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benthological;

4-(2-{1-benzhydryl-5-chloro-2-[2-(2-chlorophenylsulfonyl)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(4-chloro-2-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-[2-(1-benzhydryl-2-{2-[(benzylmethyl)amino]ethyl}-5-morpholine-4-yl-1H-shall ndol-3-yl)ethoxy]benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-cyanobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-cyanobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3-cyanobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl)ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(4-cyanobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-({[4-(1-piperidinylcarbonyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-(2-{2-[2-({[4-(aminosulfonyl)benzyl]sulfonyl}amino)ethyl]-1-benzhydryl-5-chloro-1H-indol-3-yl}ethoxy)benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-(4-methanesulfonylaminoethyl)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-(4-diethylaminoethylmethacrylate)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-phenylmethanesulfonyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3,5-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-[(methyl who sulfonyl)amino]ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-{2-[(phenylsulfonyl)amino]ethyl}-1H-indol-3-yl]ethoxy}benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-({[3-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

2-{[(2-{[(2-{1-benzhydryl-3-[2-(4-carboxyphenoxy)ethyl]-5-chloro-1H-indol-2-yl}ethyl)amino]sulfonyl}ethyl)amino]carbonyl}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[pyridin-3-elmersolver]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[pyridin-4-elmersolver]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[pyridin-2-elmersolver]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(cyclohexylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(4-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid; and

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(4-terbisil)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-(3-{1-benzhydryl-5-chloro-2-[2-({[4-(trifluoromethyl)Ben is Il]sulfonylamino)ethyl]-1H-indol-3-yl}propyl)benzoic acid;

4-(3-{1-benzhydryl-5-chloro-2-[2-({[3-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(4-chlorbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-pyridinylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-pyridinylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(4-pyridinylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-Chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-Chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,5-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-methoxybenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{3-[2-(2-{[(2-aminobenzyl)sulfonyl]amino}ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-methylbenzyl)sulfonyl]amino}ethyl)-1H-in the ol-3-yl]propyl}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(4-cryptomaterial)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-fluoro-6-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,5-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-diferensial)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-({[(6-chloro-3-pyridinyl)methyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-({[(5,6-dichloropyridine-2-yl)methyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3-methoxybenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,5-dimethylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-methylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-({[(phenylsulfanyl)methyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-(26 dimethylaminoethylmethacrylate)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-(2-methoxybenzenesulfonamide)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-[2-(1-benzhydryl-5-chloro-2-{2-[({[(2-chloro-6-were)sulfanyl]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-(3,5-dichlorobenzenesulfonyl)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-(3,4-dimethoxybenzenesulfonamide)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-(2-morpholine-4-retentionfeeling)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-(2-pyrazole-1-retentionfeeling)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-(2-phenylenesulfonyl)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-[2-(1-benzhydryl-5-chloro-2-{2-[({2-[4-(2-pyridinyl)-1-piperazinil]ethyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(1H-1,2,4-triazole-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(3,5-dimethyl-1H-pyrazole-1-yl)ethyl]sulfonyl}am the but)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(3-methyl-1H-pyrazole-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid; and

4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(4-methyl-1H-pyrazole-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-[2-(1-benzhydryl-5-chloro-2-{2-[({2-[(2R,6S)-2,6-dimethyl-1-piperidinyl]ethyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(2-thioxo-1-imidazolidinyl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(1,3-thiazolidin-3-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-(2-[1,2,3]triazole-1-retentionfeeling)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-(3-{1-benzhydryl-5-chloro-2-[2-(2-morpholine-4-retentionfeeling)ethyl]-1H-indol-3-yl}propyl)benzoic acid;

4-[3-(1-benzhydryl-5-chloro-2-{2-[2-(2,6-dimethylpiperidin-1-yl)ethanolgasoline]ethyl}-1H-indol-3-yl)propyl]benzoic acid;

4-[3-(1-benzhydryl-5-chloro-2-{2-[2-(3,5-dimethylpyrazol-1-yl)ethanolgasoline]ethyl}-1H-indol-3-yl)propyl]benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-(2-tetrazol-2-retentionfeeling)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-(2-tetrazol-1 retentionfeeling)ethyl]-1H-indol-3-yl}this is XI)benzoic acid;

4-{2-[1-benzhydryl-6-chloro-2-(2-phenylmethanesulfonyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-(2-{1-benzhydryl-6-chloro-2-[2-(3,4-dichlorobenzenesulfonyl)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-(2-{1-benzhydryl-6-chloro-2-[2-(3,5-dichlorobenzenesulfonyl)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-cyanobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(tetrahydro-2H-Piran-2-ylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-2-(2-{[(1,3-benzoxazol-2-ylmethyl)sulfonyl]amino}ethyl)-5-chloro-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(cyanomethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3-thienylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-[2-(1-benzhydryl-5-chloro-2-{2-[2-(2-methylpyrrolidine-1-yl)ethanolgasoline]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid;

4-[2-(1-benzhydryl-5-chloro-2-{2-[2-(2-methylpiperidin-1-yl)ethanolgasoline]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid;

4-[2-(1-benzhydryl-5-chloro-2-{2-[2-(2,5-dimethylpiperidin-1-yl)ethanolgasoline]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid;

4-(2-{1-benzhydryl-5-CHL is R-2-[2-(2-thiomorpholine-4-retentionfeeling)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-(2-piperidine-1-retentionfeeling)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-o-thailandandparticularlywomen)-1H-indol-3-yl]ethoxy)benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-(2-chlorpheniramineethscopolamine)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-(2,6-dichlorobenzenesulfonyl)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-(2,5-dimethoxyphenylethylamine)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-[2-(1-benzhydryl-5-chloro-2-{2-[2-(3-hydroxypyrrolidine-1-yl)ethanolgasoline]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid;

4-[2-(1-benzhydryl-5-chloro-2-{2-[2-(4-hydroxypiperidine-1-yl)ethanolgasoline]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-(2-pyrrolidin-1 retentionfeeling)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-[2-(1-benzhydryl-5-chloro-2-{2-[2-(2-dimethylaminomethylene-1-yl)ethanolgasoline]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-(2-imidazol-1-retentionfeeling)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-diferensial)sulfonyl]amino}ethyl)-1H-indol-3-yl]impregnated the}benzoic acid;

4-{3-[1-benzhydryl-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoic acid;

3-(4-{[2-(1-benzhydryl-2-{2-[(benzylmethyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethyl]sulfonyl}phenyl)propanoic acid;

3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-diferensial)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoic acid;

3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-terbisil)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoic acid;

3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-Chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoic acid;

4-({[(1-benzhydryl-2-{2-[(benzylmethyl)amino]ethyl}-5-chloro-1H-indol-3-yl)methyl]amino}methyl)benzoic acid;

4-{[2-(1-benzhydryl-2-{2-[(benzylmethyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethyl]sulfonyl}benzoic acid;

4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-Chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoic acid;

4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-diferensial)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoic acid;

4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-terbisil)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoi the first acid; and

4-(2-{1-benzhydryl-5-chloro-2-[2-(2-pyrrolidin-1 retentionfeeling)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoic acid;

4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoic acid; and

4-[2-(1-benzhydryl-2-{3-[(benzylmethyl)amino]propyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoic acid;

or its pharmaceutically acceptable salt form.

26. Pharmaceutical composition having inhibitory activity against the cytosolic phospholipase A2 comprising the compound according to any one of claims 1 to 25 or its pharmaceutically acceptable salt form and a pharmaceutically acceptable carrier.

27. A method of treating inflammation in a mammal, comprising an introduction to the needy in the mammal pharmaceutically effective amount of a compound according to claims 1, 2, 3-10 or 11-25 or its pharmaceutically acceptable salt form.

28. A method of treating pain in a mammal, comprising an introduction to the needy in the mammal pharmaceutically effective amount of a compound according to any one of claims 1, 2, 3-10 or 11-25 or its pharmaceutically acceptable salt form.

29. A method of treating asthma in a mammal, comprising the introduction of the well is given in the mammal pharmaceutically effective amount of a compound according to any one of claims 1 or 2, 3-10 or 11-25 or its pharmaceutically acceptable salt form.

30. A method of treating arthritis and/or rheumatoid disorders in a mammal, comprising an introduction to the needy in the mammal pharmaceutically effective amount of a compound according to any one of claims 1, 2, 3-10 or 11-25 or its pharmaceutically acceptable salt form.

31. The method according to item 30, where the disorder is a rheumatoid arthritis.

32. The method according to item 30, where the disorder is osteoarthritis.

33. The method according to item 30, where the disorder is a disease of Steele.

34. The compound of formula (A)

where X2n, n1n2n3n4, R, R2, R3and R4are as defined in any one of claims 1 to 17; and

R' is selected from the group consisting of-OH, -NH-S(O)2-(CH2)n2-halogen, -NH-S(O)2-CH=CH2, -NH2or a protected form-NH2.

35. The connection 34, having the formula (In)

where R represents -(CH2)n-A, where a is a

;

B and C each independently selected from the group consisting of phenyl or phenyl substituted by 1-3 substituents, independently selected from the group consisting of H, halogen, -CN, -When On, -CF3, -OCF3, -OH, -C1-C6of alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), and-NO2;

R' is selected from the group consisting of-OH, -NH-S(O)2-(CH2)n2-halogen, -NH-S(O)2-CH=CH2, -NH2or a protected form-NH2;

R8and R9independently selected from H, halogen, C1-C6the alkyl and C1-C6alkoxy;

R7represents -(CH2)n4-CO1N or C1-C6alkilany ether -(CH2)n4-CO2N;

R3selected from H, halogen and-NO2;

R4selected from H, halogen, morpholino;

n is an integer from 0 to 3;

n1an integer from 0 to 3;

n2an integer from 0 to 3;

n3an integer from 0 to 3;

n4an integer from 0 to 2; and

X is a linking group selected from the group consisting of-O-, -CH2-, -SO2-, -NH - and-N(C1-C6alkyl)-.

36. The connection 34 or 35, where the halogen atom in the R' group-NH-S(O)2-(CH2)n2halogen represents bromine or chlorine.

37. The connection 34, having the formula (D)

where X, n4, R3, R4and R8-15 are as defined in clause 34.

38. The connection 34, having the formula (E)

where X, R3and R4are as defined in clause 34, and

R10-R15independently selected from H, halogen, -CN, -Cho, -CF3, -OCF3, -OH, -C1-C6of alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -N-C(O)-( C1-C6alkyl) or-NO2.

39. The connection clause 37 or 38, where R10-R15each represent N.

40. The connection 34, which represents one of the following:

methyl ester of 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]econsultancy}benzoic acid;

methyl ester of 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoic acid;

methyl ester of 4-{3-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoic acid;

methyl ester of 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethylamino}benzoic acid;

methyl ester of 4-({2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}methylamino)benzoic acid.

41. The compound according to claim 1, where the compound is selected from the group consisting of:

4-{[2-(1-benzhydryl-2-{2-[(benzylmethyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethyl]amino}benzoic acid;/p>

4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chloro-6-were)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}amino)benzoic acid;

4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-methoxyphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}amino)benzoic acid;

4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}amino)benzoic acid;

4-[[2-(1-benzhydryl-2-{2-[(benzylmethyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethyl](methyl)amino]benzoic acid;

4-[{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}(methyl)amino]benzoic acid;

4-[{2-[1-benzhydryl-5-chloro-2-(2-{[(2-chloro-6-were)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}(methyl)amino]benzoic acid;

4-[{2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}(methyl)amino]benzoic acid;

4-[{2-[1-benzhydryl-5-chloro-2-(2-{[(2-methoxyphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}(methyl)amino]benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,4-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,4,6-trichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{3-[1-Bencher is l-5-chloro-2-(2-{[(2-cyanophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-(3-{2-[2-({[2-(aminomethyl)phenyl]sulfonyl}amino)ethyl]-1-benzhydryl-5-chloro-1H-indol-3-yl}propyl)benzoic acid;

4-[3-(1-benzhydryl-2-{2-[(1,1'-biphenyl-2-ylsulphonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)propyl]benzoic acid;

4-{3-[1-benzhydryl-2-(2-{[(2-bromophenyl)sulfonyl]amino}ethyl)-5-chloro-1H-indol-3-yl]propyl}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,4-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,4,6-trichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-cyanophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-(2-{2-[2-({[2-(aminomethyl)phenyl]sulfonyl}amino)ethyl]-1-benzhydryl-5-chloro-1H-indol-3-yl}ethoxy)benzoic acid;

4-[2-(1-benzhydryl-2-{2-[(1,1'-biphenyl-2-ylsulphonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoic acid;

4-{2-[1-benzhydryl-2-(2-{[(2-bromophenyl)sulfonyl]amino}ethyl)-5-chloro-1 H-indol-3-yl]ethoxy}benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(5-chloro-2,4-differenl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-methoxy-4-were)sulfonyl]amino}e who yl)-1H-indol-3-yl]propyl}benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(4-chloro-2,5-differenl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(5-chloro-2,4-differenl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(4-chloro-2,5-differenl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-methoxy-4-were)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(7-chloro-2,1,3-benzoxadiazole-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(7-methoxy-2,1,3-benzoxadiazole-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{2-(1-benzhydryl-5-chloro-2-(2-{[(7-chloro-2,1,3-benzoxadiazole-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(7-methoxy-2,1,3-benzoxadiazole-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-(3-{1-benzhydryl-5-chloro-2-[2-({[5-(2-methyl-1,3-thiazol-4-yl)Tien-2-yl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-({[5-(2-methyl-1,3-thiazol-4-yl)Tien-2-yl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-[2-(1-benzhydryl-5-chloro-2-{2-[(Tien-3-ylsulphonyl)amino]ethyl}-1H-indol-3-the l)ethoxy]benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(6-morpholine-4-espiridion-3-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-[3-(1-benzhydryl-5-chloro-2-{2-[(Tien-3-ylsulphonyl)amino]ethyl}-1 H-indol-3-yl)propyl]benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(6-morpholine-4-espiridion-3-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-(2-{1-benzhydryl-2-[2-(benzo[1,2,5]oxadiazol-4-sulfonylamino)ethyl]-5-chloro-1H-indol-3-yl}ethoxy)benzoic acid;

4-(3-{1-benzhydryl-2-[2-(benzo[1,2,5]oxadiazol-4-sulfonylamino)ethyl]-5-chloro-1H-indol-3-yl}propyl)benzoic acid;

4-(2-{1-benzhydryl-2-[2-(2-benzoyloxymethyl)ethyl]-5-chloro-1H-indol-3-yl}ethoxy)benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-(2-isopropoxybenzonitrile)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-(3-{1-benzhydryl-5-chloro-2-[2-(2-isopropoxybenzonitrile)ethyl]-1H-indol-3-yl}propyl)benzoic acid;

4-(3-{1-benzhydryl-2-[2-(2-benzoyloxymethyl)ethyl]-5-chloro-1H-indol-3-yl}propyl)benzoic acid;

4-(3-{1-benzhydryl-2-[2-(2-hydroxybenzylideneamino)ethyl]-1H-indol-3-yl}propyl)benzoic acid;

4-(3-{1-benzhydryl-5-chloro-2-[2-(2-hydroxybenzylideneamino)ethyl]-1H-indol-3-yl}propyl)benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-(2-chlorbenzoyl is ylamino)ethyl]-1H-indol-3-yl}ethoxy)-2-fermenting acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-(2-chloro-6-methylbenzenesulfonamide)ethyl]-1H-indol-3-yl}ethoxy)-2-fermenting acids;

N-[2-(1-benzhydryl-5-chloro-3-{2-[4-(2H-tetrazol-5-yl)phenoxy]ethyl}-1H-indol-2-yl)ethyl]-1-(3,4-dichlorophenyl)methanesulfonamide;

N-[2-(1-benzhydryl-5-chloro-3-{2-[4-(2H-tetrazol-5-yl)phenoxy]ethyl}-1H-indol-2-yl)ethyl]-2-chlorobenzenesulfonamide;

N-[2-(1-benzhydryl-5-chloro-3-{2-[4-(2H-tetrazol-5-yl)phenoxy]ethyl}-1H-indol-2-yl)ethyl]butane-1-sulfonamida;

N-[2-(1-benzhydryl-5-chloro-3-{2-[4-(2H-tetrazol-5-yl)phenoxy]ethyl}-1H-indol-2-yl)ethyl]-2,2,2-cryptgethashparam;

4-(2-{1-benzhydryl-5-chloro-2-[2-(2,4,6-tripersonality)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-(4-methoxy-2-nitrobenzenesulfonamide)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-(3-triftormetilfullerenov)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-(3-{1-benzhydryl-5-chloro-2-[2-(2,4,6-tripersonality)ethyl]-1H-indol-3-yl}propyl)benzoic acid;

4-(3-{1-benzhydryl-5-chloro-2-[2-(4-methoxy-2-nitrobenzenesulfonamide)ethyl]-1H-indol-3-yl}propyl)benzoic acid; and

4-(3-{1-benzhydryl-5-chloro-2-[2-(3-triftormetilfullerenov)ethyl]-1H-indol-3-yl}propyl)benzoic acid,

or the pharmaceutically priemysel.

42. The compound according to claim 1, where the compound is selected from the group consisting of

4-(2-{1-benzhydryl-5-chloro-2-[2-({[4-(methylsulphonyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl)ethoxy)benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(methylsulphonyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-[2-(1-benzhydryl-2-{2-[(1,1'-biphenyl-3-ylsulphonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(5-methyl-1-phenyl-1H-pyrazole-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(1,3,5-trimethyl-1H-pyrazole-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(1,3,5-trimethyl-1H-pyrazole-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,3-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,3-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(4'-fluoro-1,1'-biphenyl-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(4'-fluoro-1,1'-biphenyl-4-yl)su is hanil]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-({[3-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-[2-(1-benzhydryl-5-chloro-2-{2-[({[(3,4-dichlorophenyl)thio]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid;

4-[2-(1-benzhydryl-5-chloro-2-{2-[({[(3-chloro-4-forfinal)thio]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-forfinal)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-differenl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-chloro-6-were)sulfonyl])amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-(2-{[(4-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-(2-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-(triptoreline)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-were)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-methoxyphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-2-(2-{[(2-tert-butylphenyl)sulfonyl]amino}ethyl)-5-chloro-1H-indol-3-yl]ethoxy}benzoic acid; and

4-(2-{1-benzhydryl-5-chlor-[2-({[2-(methylthio)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid,

or its pharmaceutically acceptable salt.

43. The compound according to claim 1, where the compound is selected from the group consisting of

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3-chloro-2-were)sulfonyl]amino}ethyl)-1H-indol-3-yl}ethoxy}benzoic acid;

4-[2-(2-{2-[2-(4-acetyl-piperazine-1-yl)ethanolgasoline]ethyl}-1-benzhydryl-5-chloro-1H-indol-3-yl)ethoxy]benzoic acid;

4-[2-(1-benzhydryl-5-chloro-2-{2-[2-(3,5-dimethylpiperazine-1-yl)ethanolgasoline]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid;

4-[2-(2-{2-[2-(4-acetyl-3,5-dimethylpiperazine-1-yl)ethanolgasoline]ethyl}-1-benzhydryl-5-chloro-1H-indol-3-yl)ethoxy]benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(4-methylpiperidin-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(3-methylpiperidin-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-[2-(1-benzhydryl-2-{2-[2-(2-carbamoylation-1-yl)ethanolgasoline]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoic acid;

4-[2-(1-benzhydryl-5-chloro-2-{2-[({2-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]ethyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(2-ethylpiperidine-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-[2-(1-benzhydryl-5-chloro-2-{2-[({2-[(3R,5S) - for 3,5-dimethylocta the Jn-4-yl]ethyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(2-isopropylpyrimidine-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(2-methyl-3-oxopiperidin-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3-chloro-4-were)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-chloro-4-were)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}be what sainoi acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3-chloro-5-fluoro-2-were)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-chloro-5-fluoro-2-were)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-nitrophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-nitrophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-[2-(1-benzhydryl-5-chloro-2-[2-[(methylsulphonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid;

4-(3-{1-benzhydryl-5-chloro-2-[2-(2,4,6-trimethylbenzenesulfonamide)ethyl]-1H-indol-3-yl}propyl)benzoic acid;

4-(3-{1-benzhydryl-5-chloro-2-[2-({[2-fluoro-6-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid;

4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-fluoro-6-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimetilfenil)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimetilfenil)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-diethylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-diethylphenyl is)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-acid)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-acid)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid; and

4-[2-(1-benzhydryl-2-{2-[(benzylmethyl)amino]ethyl}-5-nitro-1H-indol-3-yl)ethoxy]benzoic acid,

or a pharmaceutically acceptable salt.

44. The compound according to claim 1, where the compound is selected from the group consisting of

4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(2-chloro-1-methylethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-[3-(1-benzhydryl-5-chloro-2-{2-[(cyclopropylmethyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-phenylethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-phenylethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

3-(2-(1-benzhydryl-5-chloro-(2-(2-phenylmethylsulfonyl)ethyl)-1H-indol-3-yl)ethoxy)benzoic acid;

3-(2-(1-benzhydryl-5-chloro-2-(2-(3,4-dichlorophenyl)methylsulfonylamino)ethyl)-1H-indol-3-yl)ethoxy)benzoic acid;

3-(2-(1-benzhydryl-5-chloro-2-(2-phenylmethylsulfonyl)ethyl)-1H-indol-3-yl)et the XI)benzoic acid;

3-(2-(1-benzhydryl-5-chloro-2-(2-((3,4-dichloro-phenyl)methylsulfonyl)ethyl)-1H-indol-3-yl)ethoxy)benzoic acid;

4-[2-(1-benzhydryl-5-chloro-2-{2-[({[(2,4-dichlorophenyl)sulfanyl]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid;

4-[2-(1-benzhydryl-5-chloro-2-{2-[({[(2,4-differenl)thio]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid;

4-[2-(1-benzhydryl-5-chloro-2-{2-[({[(3,4-dichlorophenyl)sulfinil]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-hydroxyphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

N-{2-[1-benzhydryl-5-chloro-3-(2-{4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ilidene)methyl]phenoxy}ethyl)-1H-indol-2-yl]ethyl}-1-(3,4-dichlorophenyl)methanesulfonamide;

N-[2-(1-benzhydryl-5-chloro-3-{2-[4-(2,4-dioxothiazolidine-5-ylidenemethyl)phenoxy]ethyl}-1H-indol-2-yl)ethyl]-2-methylbenzenesulfonamide;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(1-methyl-1H-imidazol-2-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(1-methyl-1H-imidazol-2-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

4-{3-[1-benzhydryl-2-(2-{[(2-chlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]this is si}-2-fermenting acid;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-Chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-fermenting acids;

3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]-2,2-dimethylpropanoate acids;

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-methoxybenzoic acid; and

4-{2-[1-benzhydryl-5-chloro-2-(2-{((3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-isopropoxybenzoic acid,

or its pharmaceutically acceptable salt.

45. The compound according to claim 1, where the compound is selected from the group consisting of

4-{3-[5-chloro-1-(diphenylmethyl)-2-(2-{[(2-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-(3-{1-benzhydryl-5-chloro-2-[2-({[4-(methylsulphonyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid;

4-(3-{1-benzhydryl-5-chloro-2-[2-({[2-(methylsulphonyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid;

4-[3-(1-benzhydryl-2-{2-[(1,1'-biphenyl-3-ylsulphonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)propyl]benzoic acid;

4-(3-{1-benzhydryl-5-chloro-2-[2-({[2-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(5-methyl-1-phenyl-1H-pyrazole-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]n the sawdust}benzoic acid;

4-(3-{1-benzhydryl-5-chloro-2-[2-({[3-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-forfinal)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{3-[5-chloro-2-(2-{[(2,6-differenl)sulfonyl]amino}ethyl)-1-(diphenylmethyl)-1H-indol-3-yl]propyl)benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-chloro-6-were)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-(3-{1-benzhydryl-5-chloro-2-[2-({[4-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid;

4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-(triptoreline)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-were)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-methoxyphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

4-{3-[1-benzhydryl-2-(2-{[(2-tert-butylphenyl)sulfonyl]amino}ethyl)-5-chloro-1H-indol-3-yl]propyl}benzoic acid;

4-(3-{1-benzhydryl-5-chloro-2-[2-({[2-(methylthio)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid;

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-chloro-2-were)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid; and

4-(3-{1-benzhydryl-5-chloro-2-[2-({[2-(2-chloro-1-IU is retil)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid,

or its pharmaceutically acceptable salt.



 

Same patents:

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to new compounds with formula I, their pharmaceutical salts and to complex esters. The invented compounds have inhibiting propertied towards catepsin K and can be used for making medicinal preparations for curing diseases and conditions, in which catepsin K is involved, for example, inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis and tumorous diseases. In general formula I R represents H, R13 represents (inferior)alkyl, C3-C10cylcloalkyl or C3-C10cycloalkyl(inferior)alkyl, each of which is independently optionally substituted with a halogen atom, hydroxyl, CN, NO2 or optionally mono- or di(inferior)alkyl substituted amino group; and R14 represents H or optionally substituted phenyl, phenyl-W-, phenyl(inferior)alkyl-W-, C3-C10cycloalkyl, C3-C10cycloalkyl-W-, N-heterocyclyl, N-heterocyclyl -W-. Substitutes of the indicated values of radicals are shown in the formula of invention. The invention also relates to methods of obtaining the compounds.

EFFECT: obtaining pyrrolopyrimidines with inhibiting properties towards catepsin K, which can be used for making medicinal preparations for curing diseases and conditions, in which catepsin K is involved.

4 cl, 59 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): their using (variants) for preparing a drug used in treatment of diseases modulation of activity of chemokine receptors is useful, and to a pharmaceutical composition modulating chemokine receptors and comprising abovementioned compound. In compound of the formula (I) m = 0 or 1; R1 means halogen atom; X, Y and Z represent independently a bond, -CH2- or -O-, or X and Y form in common -CH=C(CH3)- or -C(CH3)=CH- under condition that only one radical among X, Y and Z can represents a bond, and under condition that X and Y both don't represent -O- simultaneously; n = 0, 1 or 2; R2 represents halogen atom, or (C1-C6)-alkyl; q = 0 or 1; R3 represents -NHC(O)R10, -C(O)NR11R12 or -COOR12a; each radical among R4, R5, R6, R7 and R8 represents independently hydrogen atom (H) or (C1-C6)-alkyl; t = 0, 1 or 2; R9 represents halogen atom, -OH, -COOH, (C1-C6)-alkoxy group, (C1-C6)-alkoxycarbonyl; R10 represents group (C1-C6)-alkyl, (C3-C6)-cycloalkyl, or R10 represents -NR14R15; each R11 and R12 represents independently (1) H; (2) 3-6-membered saturated cycloalkyl or phenyl or 5-membered unsaturated heterocyclyl comprising from 1 to 4 heteroatoms N wherein indicated cycloalkyl, phenyl and heterocyclyl are substituted possibly with one or two substitutes chosen from -OH, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl; (3) (C1-C6)-alkyl substituted possibly at least with one substitute chosen from halogen atom, -OH, -COOH, (C1-C6)-alkylcarbonylamino group, phenyl, 5-membered unsaturated heterocyclyl comprising oxygen atom (O), or from 1 to 2 N atoms, bicycloheptyl wherein this phenyl, heterocyclyl or bicycloheptyl is substituted possibly at least with one substitute chosen from halogen atom, -OH, =O, or (4) (C1-C6)-alkylsulfonyl, or R11 and R12 in common with N atoms to which they are bound form 5-membered unsaturated heterocyclyl comprising one N atom or 5-6-membered heterocyclyl comprising from 1 to 2 heteroatoms, such as S, O and N, or 5-6-membered saturated heterocyclyl, ortho-condensed with benzene ring and comprising one N atom and wherein indicated heterocyclic systems are substituted possibly with one or two substitutes chosen from halogen atom, (C1-C6)-alkyl, (C1-C6)-hyroxyalkyl, (C1-C6)-halogenalkyl, (C1-C6)-alkylamino, di-(C1-C6)-alkylamino group, phenyl, halogenphenyl and hydroxydiphenylmethyl; R12a represents H or (C1-C6)-alkyl; each radical among R14 and R15 represents independently H or (C1-C6)-alkylsulfonyl, or R14 and R15 in common with N atom to which they are bound form 5-membered saturated heterocyclyl comprising one N atom and substituted possibly with one -OH, or its pharmaceutically acceptable salt or solvate. Also, invention relates to a method (variants) for synthesis of compound of the formula (I) according to one of the following method: by one variant, compound of the formula (II): is subjected for interaction with compound of the formula (III): by other variant, compound of the formula (IV): is subjected for interaction with compound of the formula (V): by other variant, compound of the formula (VI): wherein R3 represents -NHC(O)R10 and L1 represents a leaving group is subjected for interaction with L1C(O)R10; by other variant, compound of the formula (VIII): wherein R3 represents -C(O)NR11R12 and L2 represents a leaving group is subjected for interaction with compound of the formula (IX) given in the invention description. Also, invention relates to an intermediate compound of the formula (IIA): (wherein R1a is chosen from F, Cl, -CH3 and -CF3; s = 1 or 2; q = 0 or 1; w = 0 or 1; R2a represents F, and when q and s = 1 and w = 0 then R1a can't represent chlorine atom), and to a method for synthesis of compound of the formula (IIA) (wherein s = 1) and wherein compound of the formula (XX): is subjected for interaction with compound of the formula (XXII): (wherein R20 represent a protective group) before formation of compound of the formula (XXIV): followed by carrying out the cyclization reaction and removing the protective group R20.

EFFECT: improved methods of synthesis.

25 cl, 236 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I): wherein (a) each R1 is chosen independently from hydrogen atom and alkoxy-group; (b) R2 represents hydrogen atom; (c) each R3 and R4 is chosen independently of one another from hydrogen atom, alkyl, alkynyl, heteroalkyl group, aryl; or R3 and R4 in common with nitrogen atom bound with them form heteroaryl or heterocycloaryl substitute optionally substituted with one or more hydroxo-group, carboxyl group, keto-, thioketo-, phenyl group, alkyl, heteroalkyl group, heteroaryl, heterocycloalkyl, spirocycloalkyl and their combinations; (d) each R5 and R6 represents hydrogen atom; or optical isomers, diastereomers and enantiomers represented by above given formula, and their pharmaceutically acceptable salts also. Also, invention describes using compound of the formula (I) for preparing a pharmaceutical composition possessing antibacterial activity and antibacterial pharmaceutical composition containing the safety and effective amount of compound of the formula (I) and a pharmaceutically acceptable carrier. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable properties of compounds and pharmaceutical composition.

7 cl, 37 ex

FIELD: organic chemistry, insecticides.

SUBSTANCE: invention relates to compounds of formula I , wherein W is halogen, C1-C6-alkyl, C1-C6-alkoxy, C1-C4-haloalkyl or C1-C4-haloalkoxy; X is hydrogen, halogen, C1-C6-alkyl; Y is hydrogen, halogen, C1-C6-alkyl, C1-C4-haloalkyl, C1-C4-haloalcoxy or cyano; Z is hydrogen, halogen, etc.; G is halogen or nitro; meanings of the other substituents are as defined in specification. Also disclosed are methods for production of said compounds by interaction compounds of formula II with halogenation agents in presence of solvent and optionally of radical initiator of with fumed nitric acid in presence of solvent.

EFFECT: new compounds with insecticide activity.

17 cl, 20 tbl, 114 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of derivatives of indolinospiropyrane of the formula (1): wherein R1 means (C1-C18)-alkyl; each among R2 and R3 mean independently (C1-C4)-alkyl; R4 means hydrogen atom, hydroxy-group, trichloromethyl, trifluoromethyl formyl, (C1-C)-alkyl, halogen atom, (C1-C4)-alkoxy-, nitro-group; x = 1 or 2. Method comprises the following steps: (i) synthesis of indoline on polymeric carrier of the formula (III): wherein R1 means (C1-C18)-alkyl; each among R2 and R means independently (C1-C4)-alkyl; (ii) treatment of indoline-carrying polymeric carrier wherein this carrier represents hydroxy-resin at temperature from 50°C to 120°C in inert atmosphere for time from 14 h to 11 days with a derivative of salicylic aldehyde of the formula (VI): wherein R4 means hydrogen atom, hydroxy-group, trichloromethyl, trifluoromethyl, formyl, (C1-C4)-alkyl, halogen atom, (C1-C4)-alkoxy-, nitro-group; x = 1 or 2 to yield indolinospiropyrane compound of the formula (I), and (iii) release of indolinospiropyrane compound of the formula (I). Invention proves synthesis of novel derivatives of indolinospiropyrane possessing photochromic properties.

EFFECT: improved method of synthesis.

8 cl, 28 ex

FIELD: organic chemistry.

SUBSTANCE: invention describes C2-phenyl-substituted cyclic ketoenols of the general formula: wherein W means hydrogen atom, alkyl with 1-6 carbon atoms; X means alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms; Y means hydrogen atom, methyl, ethyl, isopropyl, alkenyl with 2-6 carbon atoms, ethynyl; Z means hydrogen atom, alkyl with 1-6 carbon atoms under condition that at least one of residues W, X, Y or Z means a chain with at least 2 carbon atoms but only one of residues X and Y can mean alkenyl with 2-6 carbon atoms; CKE means one of the following groups: , , and wherein A means hydrogen atom, alkyl with 1-6 carbon atoms; B means hydrogen atom, alkyl with 1-6 carbon atoms; A and B in common with carbon atom to which they are bound mean cycloalkyl with 5-6 carbon atoms wherein the ring carbon atom can be substituted with oxygen atom and can be substituted with alkyl with 1-6 carbon atoms or alkoxyl with 1-6 carbon atoms; A and B in common mean group of the formula: D means hydrogen atom or phenyl substituted with fluorine atom if CKE means group of the formula (4); G means hydrogen atom (a) or one of groups of the formula: or wherein R1 means alkyl with 1-6 carbon atoms, alkoxymethyl with 1-2 carbon atoms; R2 means alkyl with 1-4 carbon atoms; A and Q1 in common mean alkanediyl with 3-4 carbon atoms; Q2 means hydrogen atom. Invention provides preparing compound of the formula (I) possessing with insecticide, acaricide and herbicide activity.

EFFECT: valuable properties of compounds.

2 cl, 8 tbl, 32 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes derivative of 3,4-dihydroisoquinoline of the formula (I) or its nontoxic salt and a pharmaceutical agent comprising its as an active component (wherein all symbols have the same values as given in description). Compound of the formula (I) possesses agonistic effect on CB2-receptors and, therefore, it can be used for prophylaxis and/or treatment of different diseases, for example, asthma, nasal allergy, atopic dermatitis, autoimmune diseases, rheumatic arthritis, immune dysfunction, postoperative pain and carcinomatous pain.

EFFECT: valuable medicinal properties of derivatives.

14 cl, 33 tbl, 561 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to substituted 3-oxo-1,2,3,4-tetrahydroxinoxalines of general formula 1 , wherein R1 represents substituted sulfanyl or substituted sulfonyl group, containing as substituent optionally substituted C1-C4-alkyl, optionally substituted C3-C8-cycloalkyl, aryl-(C1-C4)alkyl optionally substituted in aril or alkyl group, heterocyclyl-(C1-C4)alkyl optionally substituted in heterocycle or alkyl group; R2 and R3 independently represent hydrogen, halogen, CN, NO2, optionally substituted hydroxyl, optionally substituted amino group, optionally substituted carboxylic group, optionally substituted carbamoyl group, optionally substituted arylcarbonyl group or optionally substituted heterocyclylcarbonyl group; R4 and R5 independently represent hydrogen or inert substituent. Claimed compounds are high effective kaspase-3 inhibitors and are useful in production of pharmaceutical compositions for treatment of diseases associated with excess apoptosis activation, as well as for experimental investigations of apoptosis in vivo and in vitro. Also disclosed are pharmaceutical composition in form of tablets, capsules or injections in pharmaceutically acceptable package, as well as method for production thereof and therapy method.

EFFECT: pharmaceutical composition for apoptosis treatment and investigation.

6 cl, 3 dwg, 8 ex, 1 tbl

FIELD: pharmaceutical chemistry, in particular pharmaceutical compositions.

SUBSTANCE: new spyro(2H-1-benzopyrane-2,4'-piperidine) derivatives of general formula I

and pharmaceutically acceptable salts thereof are disclosed. In formula dotted line is optional bond; Y is 1-4 substituents independently selected from hydrogen, halogen, C1-C4-alkyl, optionally substituted with one or more halogen, C1-C6-alkyloxy, optionally substituted with halogen or C3-C6-cycloalkyl, C2-C6-alkenyloxy, C2-C6-alkinyloxy, C3-C6-cycloalkyloxy, C6-C12-aryloxy, arylalkyloxy, pyridilmethoxy, SR3, NR3R4, OSO2R5, and NR3SO2R4; or two Y together may form O-(CH2)n-O or O-(CF2)n-O, wherein n is 1 or 2: or Y is condensed C5-C6-aryl group; X is 1-3 substituents independently selected from hydrogen, halogen, hydroxyl, C1-C6-alkoxy, and C1-C4-alkyl; R1 is hydrogen, C1-C4-alkyl, or C6-C12-aryl; R2, R3, and R4 are independently hydrogen or C1-C4-alkyl; R5 is C6-C12-aryl. Also disclosed are pharmaceutical compositions including said derivatives and having activity in relation to CNS.

EFFECT: new compounds with valuable pharmacological action.

9 cl, 1 tbl, 83 ex

The invention relates to new derivatives of galantamine General formula I:

where R1-R5, G1-G3and W have the meanings indicated in the claims, and the invention relates to a method for producing these compounds, medicinal product and the method of its production

FIELD: organic chemistry, medicine, oncology.

SUBSTANCE: invention relates to condensed heterocyclic succinamide compounds of the formula (I): , their pharmaceutically acceptable salts, solvates or isomers wherein G represents mono- or polycyclic aryl or heterocyclic group substituted possibly at one or more positions; L represents a bond, -(CR7R7')n (wherein n = 1; R7 and R7' represents independently hydrogen atom (H), alkyl or substituted alkyl) or -CH2-NH-; Z1 represents oxygen atom (O); Z2 represents O; A1 and A2 represent -CR7 or in common with R7 from group W is a heterocyclic ring wherein oxygen represents a heteroatom; Y represents -O-, -SO-, -N(V2)-, -CH2-N(V2)-, -CO-N-(alkyl)-, -CH2-S-, -CH2-SO2-; V2 represents hydrogen atom, alkyl, arylalkyl, -CO-alkyl, -CO-O-aryl, -CO-O-arylalkyl; W represents -CR7R7'-CR7R7'-, -CR7R7'-C=O, -NR9-, -CR7R7'-, -N=CR8-, -N=N, -NR9-NR9'-, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo- or substituted heterocyclo-group, aryl or substituted aryl wherein if W doesn't mean -NR9-CR7R7'-, -N=CR8-, -N=N, -NR9-NR9'- or heterocyclo- or substituted heterocyclo-group then Y must mean -O-, -CH2-S-, -SO-, -CH2-SO2-, -N-(V2)- or -CH2-N-(V2)-; Q1 and Q2 represent hydrogen atom (H). Also, invention describes a method for synthesis of intermediate compounds in synthesis of compounds of the formula (I), using the latter for preparing agents modeling function of the nuclear hormone receptors. Compounds of the formula (I) can be used in treatment of prostate cancer.

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

8 cl, 11 tbl, 463 ex

Amid derivative // 2336273

FIELD: chemistry.

SUBSTANCE: invention relates to amid derivatives of formula (I), method of disease treatment and pharmaceutical composition based on them. Compounds can be applied in treatment of different herpes virus infections. In general formula (I) , Z: 1,2,4-oxydiazol-3-yl, 4-oxazolyl, 1,2,3-triazol-2-yl or 2-pyridyl, A: phenyl, which can have a substitute (substitutes) selected from group, including lower alkyl, halogen, halogen-substituted lower alkyl, O-lower alkyl, O-lower alkylene -OH, CN, OH, O-lower alkylene-phenyl, O-lower alkylene-O-lower alkyl, NH2, NH-lower alkyl, N-(lower alkyl)2 ,NH-lower alkylene-OH, NH-lower alkylene-O-lower alkyl, O-lower alkylene- NH2, O-lower alkylene-NH-lower alkyl and O-lower alkylene-N(lower alkyl)2; heteroaryl, representing monocyclic 6-member ring, which contains nitrogen atom as heteroatom or bicyclic 9-member ring, containing 1-2 heteroatoms selected from nitrogen and/or sulfur, which can have a substitute (substitutes), selected from lower alkyl; or phenyl group, condensed with saturated 5-member hydrocarbon cycle; or phenyl group, condensed with saturated 5-member heterocyclic cycle, which contains 1-2 heteroatoms, selected from nitrogen and/or oxygen, which can have a substitute (substitutes), selected from group, including lower alkyl, halogen, -C(O)-lower alkyl, lower alkylene-O-lower alkyl, on condition, that aryl group, condensed with saturated hydrocarbon cycle or aryl group, condensed with saturated heterocyclic cycle is bound with nitrogen atom through carbon atom in aromatic cycle, X: CO, R3: C3-C6cycloalkyl, which can have a substitute (substitutes), selected from group, which includes oxo, OH, halogen, CN, O-lower alkyl, -C(O)-NH2, -C(O)-NH-lower alkyl, -C(O)-N(lower alkyl)2, lower alkylene-OH, lower alkylene-O-lower alkyl; aryl, selected from phenyl, naphtyl, which can have a substitute (substitutes), selected from halogen; pyridyl; 9-member bicyclic heteroaryl, containing 1-3 heteroatoms, selected from S, N, O; or saturated heterocyclic group, representing monocyclic 6-member group, which contains 1-2 heteroatoms selected from S, SO, SO2, N, O, which can have a substitute (substitutes), selected from halogen.

EFFECT: obtaining amid derivatives that can be applied for treating various herpes virus infections.

17 cl, 26 tbl, 125 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method for obtaining 5-{2-[5-{2-[1,3,5-ditiazinan-5-il]ethyl}-4-methyl-1,3,5-tiadiazinan-3-il]ethyl} 1,3,5-ditiazinan with formula including interaction of methyltriethyltetaraamin with water solution of formaldehide saturated with hydrogen sulphide. The given compound can find application as selective sorbents and extragents of precious metals and special reagents for inhibition of vital functions of bacteria in various technological media.

EFFECT: efficient method for obtaining 5-{2-[5-{2-[1,3,5-ditiazinan-5-il]ethyl}-4-methyl-1,3,5-tiadiazinan-3-il]ethyl} 1,3,5-ditiazinan.

1 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) and their pharmaceutically acceptable salts. The compounds claimed by the invention have inhibition effect on VR1 receptor activation and can be applied in pain prevention or treatment. In the general formula (I) , or , L is a low alkylene, E cycle is benzene or 5-membered heteroaromatic ring containing sulfur atom as a heteroatom, D cycle is a monocyclic or bicyclic hydrocarbon cycle optionally condensed with C5-7 cycloalkyl, 6-membered monocyclic heteroaromatic cycle containing nitrogen atom as heteroatom or 9-11-membered bicyclic heteroaromatic cycle containing 1 to 3 equal or different heteroatoms selected out of the group including N, S and O, G cycle is a 5-7-membered monocyclic saturated or partially saturated heterocycle or 10-membered bicyclic heterocycle containing 1 to 3 equal or different heteroatoms selected out of the group including N, S and O. The invention also concerns pharmaceutical composition based on the said compounds, and application thereof in obtaining pain prevention or treatment medication, and a method of pain prevention or treatment.

EFFECT: obtaining prevention or treatment medium against pain.

24 cl, 470 ex, 41 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the new compounds presented by the following formula (I), or to the pharmaceutically acceptable salts: , where R1 and R2 represent substitutes, adjoining with each other and with two carbonic atoms, to each of which they are adjoined forming the group presented by the following formula: 1) , or

2) , , , , , , , , or

3) or

4) , , or

where hydrogen atom in each cyclic group can be substituted bi 1-4 substitutes selected fro the following group of substitutes B1, R3 represents hydrogen atom or methyl group; and R6 represents substitute selected from the following group of A1 substitutes, the group of A1 substitutes: (1) hydrogen atom, (2) C1-C6 alkoxy group; substitute B1 group: (1) hydrogen atom, (2) hydroxyl group, (3) oxo group, (4) C1-C6 alkanoyl group, (5) C3-C8 cycloalkyl group, (6) C1-C6 alkyl group (where C1-C6 alkyl group can be substituted by C1-C6 alkoxy group), (7) C1-C6 alkoxy group, (8) C1-C6 alkoxyimino group, (9) C5-C6 cycloalkyl group, derived by two C1-C3 alkyl groups joined to the same carbonic atom with hydrogen atom and the carbons. The invention is also relates to the pharmaceutical composition.

EFFECT: production of the new biologically active compounds and pharmaceutical compositions on their basis having inhibitor potency towards to serotonine1A receptor.

34 cl, 73 ex, 12 tbl, 4 dwg

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to compounds with formula (I), their pharmaceutical salts or N-oxide used as an inhibitor to replication and/or proliferation of HCV, to the method of inhibiting replication or proliferation of hepatitis C virion using formula (I) compounds, as well as to pharmaceutical compositions based on them. The compounds can be used for treating or preventing infections, caused by hepatitis C virus. In general formula (I) cycle B is an aromatic or non-aromatic ring, which contains two heteroatoms, where X and Y, each is independently chosen from C, CH, N or O, under the condition that, both X and Y are not O and that, both X and Y are not N; U and T represent C; Z represents -CH-; A represents N or -CR2-; B represents -CR3-; D represents N or -CR4-; E represents N or -CR5-; G represents N or -CR6-; J represents N or -CR14-; K represents -CR8-; L represents N or -CR9-; M represents N or -CR10-; R2 and R6, each is independently chosen from a group, consisting of hydrogen, halogen, C1-C6alkyl, substituted C1-C6alkyl, C1-C6alkoxy, C1-C6substituted alkoxy, C1-C6alkoxycarbonyl, cycloheteroalkyl, substituted cycloheteroalkyl, -O-carbamoil, substituted -O-carbamoil, halogen C1-C6alkyl, diC1-C6alkylamino, substituted diC1-C6alkylamino and sylye ethers, where cycloheteroalkyl is a 3-7-member ring, containing 1-2 heteroatoms, chosen from N and O, under the condition that, one of R2 and R6 is not hydrogen; R3 and R5, each is independently chosen from a group, consisting of hydrogen, halogen; R4 represents hydrogen; R7 represents - NR11C(O)R12; R8, R9, R10 and R14, each is independently represents hydrogen; R11 represents hydrogen, C1-C6alkyl; and R12 is chosen from a group, consisting of halogen C1-C6alkyl; where each substituted group is substituted with one or more groups, chosen from -Q, -R40, -OR40, -C(O)R40, -C(O)OR40, where each Q independently represents halogen, R40 and R41 are independently chosen from a group consisting of hydrogen, C1-C6alkyl, C1-C6alkoxy, under the condition that: (i) at least one of A, D, E, G, J, L or M represents N; (ii) not more than one of A, D, E or G represents N; and (iii) not more than one of J, L or M represents N.

EFFECT: obtaining pyridyl-substituted heterocycles for treating and preventing infections, caused by hepatitis C virus.

33 cl, 85 dwg, 101 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the bonds of the formula (I) and their pharmaceutically acceptable salts in the capacity of modulators of receptors CB1 and to the pharmacological composition on their basis. Bonds can be used for treatment and prophylaxis of diseases, which are associated with the modulation of receptor CB1, for example, obesity and diabetes of type II. In the general formula (I) R1 means hydrogen or the lowest alkyl; R2 means hydrogen, the lowest alkyl, the lowest alkenyl, the lowest alkoxy-lowest alkyl, the lowest alkoxycarbonilamino-group or - (CH2)m-R2a; or R1 and R2 form together with atom of nitrogen to which they are attached, a 5-or 6-member saturated heterocyclic ring; R2a means cycloalkyl, which is not necessarily mono- or tetra-substituted independently by hydroxy-group, the lowest alkyl; C3-6cycloalkenyl, 5- or 6-member monovalent saturated heterocyclic ring, which contains from one to two heteroatoms, independently selected from nitrogen and oxygen; 5- or 6-member monovalent heteroaromatic ring, which contains from one to two heteroatoms, independently selected from nitrogen and oxygen, here note that the said heteroaromatic ring is not necessarily mono-substituted independently with the lowest alkyl; or phenyl which is not necessarily mono- or di-substituted independently with the lowest of the alkoxy group, halogen, halogenated lowest alkyl, halogenated lowest alkoxy group or nitro-group; R3 means the lowest alkyl, the lowest alkoxy-lowest alkyl, diphenyl-lowest alkyl or - (CH2)n-R3a; R3a means C3-6cycloalkyl which can be not necessarily condensed with the phenol ring; or C3-6cycloalkyl, which can be not necessarily mono-, di- or trisubstituted independently hydroxy-group, the lowest alkyl, C3-6cycloalkenyl, 5- or 6-member monovalent saturated heterocyclic ring, which contains from one to two heteroatoms, independently selected from nitrogen and oxygen, here note that the said heterocyclic rings are not necessarily mono-substituted independently by the lowest alkyl, 5- or 6-member monovalent heteroaromatic ring containing one heteroatom, independently selected from oxygen and sulfur, the aforesaid heteroaromatic ring being not necessarily mono-substituted independently with the lowest alkyl, or the phenyl, which can be not necessarily mono-, di- or trisubstituted independently by the hydroxy-group, lowest alkyl, lowest alkoxy-group, halogen, halogenated lowest alkyl, halogenated lowest alkoxy-group or nitro-group; R4 means the lowest alkyl the lowest alkoxycarbonyl; C3-6 cycloalkyl, 5- or 6-member monovalent heteroaromatic ring, which contains one or two heteroatoms, independently selected from nitrogen, the said heteroaromatic ring being not necessarily mono-substituted independently with the lowest alkyl, lowest alkoxy-group; phenoxy-lowest alkyl, in which the phenyl part is not necessarily mono-, di- or trisubstituted independently by the lowest alkoxy-group; or the phenyl, which not necessarily can be mono-, di- or trisubstituted independently, by the lowest alkyl, by the lowest alkoxy-group, by halogen, halogenated lowest alkyl, halogenated lowest alkoxy-group or nitro-group; or two adjusted substitutes of the said phenyl remainder indicate together -O-(CH2)p-O- or -(CH2)2-O-; R5 and R6 each indicates a substitute independently selected from hydrogen of lowest alkyl; R7 indicates hydrogen; m indicates 0,1 or 2; n indicates 1.

EFFECT: new bonds possess useful biological properties.

28 cl, 4 dwg, 380 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new bonds in the formula (I-0): or its pharmaceutically acceptable salts, where X represents a carbon atom or nitrogen atom; X1, X2, X3 and X4, each independently, represents a carbon atom or a nitrogen atom; ring A of the formula (II): represents tiazolil, imidazolil, izotiazolil, tiadiazolil, triazolil, oxazolil, oxadiazolil, izoxazolil, pirazinil, piridil, piridazinil, pirazolil or pirimidinil; R¹ represents aryl or represents a 4-10- membered monocyclic or bicyclic heteroring, which has in the ring from 1 to 4 heteroatoms, selected from the group, consisting of a nitrogen atom, sulphur atom and an oxygen atom, and R¹ can be independently substituted with 1-3 R4, and, when the specified heteroring is an aliphatic heteroring, then it can have 1 or 2 double bonds; R² independently represents hydroxy, formyl, -CH3-aFa, -OCH3-aFa, amino, CN, halogen, C1-6 alkyl or -(CH2)1-4OH; R3 represents -C1-6 alkyl, -(CH2)1-6-OH, -C(O)-OC1-6 alkyl, -C(O)-OC1-6 alkyl, -(CH2)1-6-NH2, cyano, -C(O)-C1-6 alkyl, halogen, -C2-6 alkenyl, -OC1-6 alkyl, -COOH, -OH or oxo; R4 independently represents -C1-6 alkyl, and the alkyl can be substituted with identical or different 1-3 hydroxyls, halogens, -OC(O)-C1-6 alkyls, and the alkyl can be substituted with 1-3 halogens or -OC1-6 alkyls, -C3-7 cycloalkyl, -C2-6 alkenyl, -C(O)-N(R51)R52, -S(O)2-N(R51)R52,-O-C1-6 alkyl, and C1-6 alkylcan be substituted with a halogen or N(R51)R52, -S(O)0-2-C1-6 alkyl, -C(O)-C1-6 alkyl, and C1-6 alkyl can be substituted with a halogen, amino, CN, hydroxy, -O-C1-6 alkyl, -CH3-aFa, -OC(O)-C1-6 alkyl, -N(C1-6 alkyl)C(O)O-C1-6 alkyl, -NH-C(O)O-C1-6 alkyl, phenyl, -N(R51)R52, -NH-C(O)-C1-6 alkyl, -N(C1-6 alkyl)-C(O)-C1-6 alkyl or -NH-S(O)0-2-C1-6 alkyl, -C(S)-C3-7 cycloalkyl, -C(S)- C1-6 alkyl, -C(O)-O- C1-6 alkyl, -(CH2)0-4-N(R53)-C(O)-R54, -N(R53)-C(O)-O-R54,-C(O)-aryl, it is optional to substitute the halogen, -C(O)-aromatic heteroring, -C(O)-aliphatic heteroring, heteroring, and the heteroring can be substituted with C1-6 alkyl, optionally substituting the halogen or -O-C1-6 alkyl, phenyl, optionally substituting the halogen, -C1-6 alkyl, -O-C1-6 alkyl, halogen, CN, formyl, COOH, amino, oxo, hydroxy, hydroxyamidine or nitro; R51 and R52, each independently, represents a hydrogen atom, C1-6 alkyl or a nitrogen atom, R51 and R52 together form 4-7-member heteroring; R53 represents a hydrogen atom or C1-6 alkyl, R54 represents -C1-6 alkyl or alkyls for R53 and R54 and -N-C(O)- together form 4-7-member hydrogen containing heteroring, or alkyls for R53 and R54 and -N-C(O)-O- together form 4-7-member hydrogen containing aliphatic heteroring and an aliphatic heteroring can be substituted with oxo, or an aliphatic heteroring can have 1 or 2 double bonds in the ring; X5 represents -O-, -S-, -S(O)-, -S(O)2-, a single bond or -O-C1-6 alkyl; a independently denotes a whole number 1, 2 or 3; q denotes a whole number from 0 till 2; m denotes a whole number from 0 till 2, except in the case when one of the X5 represents -O-, -S-, -S(O)- or -S(O)2-, and the other from X5 represents a single bond, and R1 represents aryl, optionally substituted with 1-3 R4, or a hydrogen containing aromatic heteroring, consisting of from 1 to 4 heteroatoms, selected from the group, comprising of a hydrogen atom, sulphur atom and an oxygen atom, in the case, when X5, both represent single bonds or in cases, when R1, both represent aliphatic heteroring. The invention also relates to the bonding in the formula (I-12), and also to the bonding in the formula (I-0), to the pharmaceutical composition, to the glucokinase activator and to the medication.

EFFECT: getting new bioactive compounds which can be used for treatment and/or prophylaxis of diabetes or obesity.

23 cl, 603 ex

FIELD: chemistry; obtaining of medicinal preparations.

SUBSTANCE: description is given of a compound with general formula where R1 represents a halogen, C1-C6alkyl, CF3, CF2H or cyano, R2 represents C1-C6alkyl, R3 represents 5- or 6 - member hetero-aryl, optionally substituted with one, two or three substitutes, chosen from a group, consisting of a halogen, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylhalogen, C1-C6alkoxy, NR'R", or substituted with a 1-morpholinyl group or substituted with thiomorpholinyl groups, 1-oxothiomorpholinyl or 1,1-dioxothiomorpholinyl; R', R" independently represent hydrogen, C1-C6alkyl, (CH2)0,1-(C3-C6)cycloalkyl, R represents hydrogen as well as its pharmaceutical salts and the method of obtaining them. The invention also relates to use of the given amidazole derivatives for obtaining medicinal preparations and to medicinal preparations containing them, meant for prevention or treatment of damages, through the mGluR5 receptor, such as acute and/or chronic neurologic damages, primarily shock pain, or for treatment of chronic and sharp pain.

EFFECT: obtaining of new compounds, with useful biological properties.

40 ex

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