UA77472C2 - Inhibitors of cytosolic phospholipase a2 - Google Patents

Abstract

This invention provides substituted indole compounds of the general formula: (I) and pharmaceutically acceptable salt forms thereof, and methods for using the compounds as inhibitors of the activity of various phospholipase enzymes, particularly phospholipase A2; enzymes, and for the medical treatment, prevention and inhibition of pain and inflammation. , (I)

Description

Description of the invention

The present invention relates to chemical inhibitors of the activity of various phospholipase enzymes, especially 2 enzymes of cytosolic phospholipase A? (cRIA5), more specifically to inhibitors of enzymes cytosolic phospholipase A2 alpha (cRI A»c), and to new M-benzhydrindole intermediate compounds for their preparation.

The invention also relates to methods of treating and alleviating asthma and symptoms of asthma and/or symptoms of arthritic or rheumatic disorders in mammals, including humans, using these chemical inhibitors.

Leukotrienes and prostaglandins are important mediators of inflammatory processes, each of which in different ways 70 contributes to the development of the inflammatory reaction. Leukotrienes recruit inflammatory cells, such as neutrophils, to the site of inflammation, promote the extravasation of these cells, and stimulate the release of tissue-damaging superoxide and proteases. Leukotrienes also play a pathophysiological role in the hypersensitivity experienced by asthmatics (see, for example, V. Zatievop ei ai., Zsiepse, 237:1171-76 (1987)). Prostaglandins increase inflammation by increasing blood flow and, therefore, leukocyte infiltration to areas of inflammation. Prostaglandins also 79 enhance the pain response caused by a stimulus.

Prostaglandins and leukotrienes are unstable and are not stored in cells, but instead are synthesized |MU.I.

Zty, Viospet. .., 259:315-324 (1989) from arachidonic acid in response to the influence of a stimulus.

Prostaglandins are produced from arachidonic acid by the action of COX-1 and COX-2 enzymes. Arachidonic acid is also a substrate for a special enzyme pathway leading to the production of leukotrienes.

Arachidonic acid, which enters these two distinct pathways of the inflammatory process, is released from the zp-2 position of membrane phospholipids by the enzymes phospholipase A" (hereinafter RI A"). It is considered to be catalyzed

RIA" reaction represents the rate-limiting stage in the process of biosynthesis, mediators of which are lipids, and the production of inflammatory prostaglandins and leukotrienes. When the phospholipid substrate "RIAo" belongs to the phosphotidylcholine class with an ether bridge in the zp-1 position, the produced lysophospholipid is the immediate precursor of platelet-activating factor (hereafter called RAE), another powerful mediator of inflammation |5.I. M/azzegtap, Nozria!| Rgasiise, 15:49-58 (1988)).

Most anti-inflammatory therapies focus on preventing the production of prostaglandins or leukotrienes by various pathways, but not on preventing the production of either. For example, ibuprofen, aspirin, and indomethacin are nonsteroidal anti-inflammatory drugs that suppress the production of prostaglandins by inhibiting COX-1/COX-2, but do not affect the inflammatory production of leukotrienes from arachidonic acid through other pathways. On the contrary, zileuton inhibits only the conversion of arachidonic acid into leukotrienes, without affecting the production of prostaglandins. None of these widely used anti-inflammatory M drugs affect the production of cancer cells. Cha

Therefore, direct inhibition of RI A 5 activity has been proposed as a useful mechanism for the drug, 32 that is, to prevent the inflammatory response. See, for example, U. Spapa ei ai!., Viospet. RIagtaso). - 36: 2429-2436 (1987).

The RI A family of enzymes, characterized by the presence of a secretion signal directed to and ultimately secreted from cells, has been sequenced and structurally determined. These secreted RIH A" have a molecular weight of approximately 14 kDa and contain seven disulfide bonds, which are necessary for activity. From 50 RIA data" are found in huge quantities in the pancreas of mammals, bee venom and various snake venoms. See, for example, references 13-15 in the work cited above.). My God. and E.A. JuOeppis, the Abomination of Oemei.

Iz" Kez., 10:205-220 (1987)) However, pancreatic enzymes are believed to have a digestive function and, by themselves, should not play an important role in the production of inflammatory mediators, whose production must be tightly regulated.

The primary structure of the first human non-pancreatic RI A was determined. This non-pancreatic and RIA" is found in platelets, synovial fluid and the spleen. It is also a secreted enzyme. -I This enzyme is a member of the above family. | See, 9U.). Zeipateg ei ai., U. Vioi.SNpet., 264:5335-5338 (1989), K.M. Kgateg ei ai., U. Vioi. Speth, 264:5768-5775 (1989) and A. Kapao et al., Viospet. Viorpuz. Kev. Shk Sott., 163: 42-48 (1989)). However, it is doubtful that this enzyme is important in the synthesis of prostaglandins, -I 20 leukotrienes and RAE, since non-pancreatic Ri A" is an extracellular protein that would be difficult to regulate, and the following enzymes in the biosynthesis pathway for these compounds are intracellular proteins. Moreover, there is evidence that RIA" is regulated by protein kinase C and c proteins (IK. Vygsp, U. Acheigod, Rhos. Mai. Asai. Zsi. O.5.A., 84: 6374-6378 (1989)), which are cytosolic proteins that must act on intracellular proteins. It would be impossible for non-pancreatic RIA » to function in the cytosol, since the high repair potential would restore 29 disulfide bonds and deactivate the enzyme.

GF) Murine RI A" was identified in a mouse macrophage cell line designated as KAMU 264.7. A specific activity equal to 2 mol/min/mg, resistant to reconstitution conditions, was reported to be associated with a molecule having a molecular weight of approximately bOkDa. However, this protein was not purified to homogeneity. | See S.S.

Ye eviye ei ai., Viospet. Viorpuz. Asia., 963:476-492 (1988)) The above-cited reference is incorporated herein by reference 60 for information relevant to the function of phospholipase enzymes, particularly RI A."

Cytosolic phospholipase A»o alpha (hereinafter "cRI Aoo") was also identified and cloned. See patents

US Patent Nos. 5,322,776 and 5,354,677, which are incorporated herein by reference in their entirety. The enzymes of these patents are intracellular RI A» enzymes, isolated from their natural source or obtained in purified form in another way, functioning intracellularly, producing arachidonic acid in response to an inflammatory stimulus.

Now that several phospholipase enzymes have been identified, it would be desirable to identify chemical inhibitors of specific phospholipase enzymes, and these inhibitors could be used to treat inflammatory conditions, particularly where it is desirable to suppress the production of prostaglandins, leukotrienes, and PAP. There remains a need to identify such anti-inflammatory agents for therapeutic use in various disease states and intermediate compounds for their preparation.

This invention covers compounds of formula (1): "You 70 that U

The same with in in: SV shchi HER. Ж п и шк к. Ше ше s шо, zany in g in de:

K is selected from the formulas -"(СН2)-А, -"СНао)д-5-А or -"СНо)1-0-А, where A is selected from the groups: ше or ше; s h i s 1

I и и и и " "и и шко. I and Esh in eV vya and k and Kk o de

O represents C.4-Ce lower alkyl, C--Ce lower alkoxy, C.sup.-Cecycloalkyl, -Cez or -"CH")4-3-Ce"c; high school

B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furanyl, thiophenyl or pyrrolyl groups, each of which is optionally substituted with 1-3, preferably 1-2, substituents independently selected from c.

Н, halogen, -СМ, -СНО, -СЕз, -ОСЕ»5, -OH, -С.-Svalkylu, -С4-Svalkoxy, -МН», -М(С.4-Svalkyl)», -МН( S.-Svalkyl), "-M-C(0)-(C4-Svalkyl), -MO", or a 5- or b--membered heterocyclic or heteroaromatic ring containing 1 or 2 heteroatoms selected from O, M or 5; or y-n is equal to a whole number from 0 to 3; ychpi is equal to a whole number from 1 to 3; po is equal to a whole number from 0 to 4; pz is equal to a whole number from 0 to Z; pa is equal to a whole number from 0 to 2; " 20 Xy selected from the chemical bond, -5-, -O-, -5(0)-, -"530)2-, -МН-, -МНО(О)-, -С-С-, ш -vs sya nya puta i dk i ci ner " with Y even || in "a y -I I ško or -I vyh i VENAH. y 1 і- i What I "Not U s den tya sa -.20 yannia p t also KK zm "B" c

Ko) in - with 99 o det i for . dey and virgins I: SE ime) and

K xYa b BC, sh y y ner - Iii still Her "and still in 65 Ki. is a group selected from C.i-Svalkyl, C.sulfofluorinated alkyl, C3-Svcycloalkyl, tetrahydropyranyl camphoryl, adamantyl, SM, -M(C.--Svalkyl)", phenyl, pyridinyl,

pyrimidinyl, furyl, thienyl, naphthyl, morpholinyl, triazolyl, pyrazolyl, piperidinyl, pyrrolidinyl, imidazolyl, piperazinyl, thiazolidinyl, thiomorpholinyl, tetrazole, indole, benzoxazole, benzofuran, imidazolidine-2-thione, 7,7-dimethylbicyclo|2.2.1) heptan-2-one, benzo|1.2.5)oxadiazole, 2-oxa-5-azabicyclo|2.2.1)heptanoic, piperazin-2-one or pyrrolyl groups, each of which is optionally substituted 1-3, preferably 1-2 substituents independently selected from H, halogen, -CM, -CHO, -SEz, -OSEz, -OH, -Si-Svalkylu, -Si-Svalkoxy, -MH", -MZh(C.4-Svalkyl) », -МН(С.--Svalkyl), -М-С(0)-(С4-Svalkyl), -MO», -505(С4-Svalkyl), -502МН», -502МН(С.4-Svalkyl ), -302M(C--Svalkyl)", -СООН, -СН.-СООН, -СН.-М(С.4-Svalkyl), -СНО-М(С.i-Svalkyl)", -СНО -MH»o, pyridine, 7/0 2-methylthiazole, morpholino, 1-chloro-2-methylpropyl, -C.-Sethioalkyl, phenyl (optionally substituted by halogens), benzyloxy, -(C4-Calkyl)C( O)SN", -(C4-Szalkil) OSN", -S(O)MN" or that B "Ye Yan then JAK Y vsta M zshke "feniv, p Mn STILL Yin and Z. and I.

Ou te y t t ze Shi vysakh as Tv v i y M sh-- JHE i: a 5 - and She y y k 0 i y o or

X»o selected from -О-, -СН»-, -35-, -50-, -505-, -МН-, -ФЩ(О)-, long and: still" Sh zno what h-

And even more

From: | I don't know. ze -

Co is a ring group selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl, or pyrrolyl, wherein the ring group is substituted with a group of the formula -(СНо)м-СОоН or a pharmaceutically acceptable acid mimetic or mimetic compound ; and, in addition, is optionally substituted with 1 or 2 -| additional substituents independently selected from H, halogen, -CM, -CHO, -CEz, -OSE»z, -OH, -C.4-Svalkylu, - -S.-Svalkoxy, -C4-Svthioalkyl, -"MH", -S(S.-Svalkyl)", -MH(S.--Svalkyl), -M-C(O0)-(C4-Svalkyl) or -MO";

Ez is selected from H, halogen, -CM, -CHO, -CEz, -OSE", -"OH, -C4-Salkyl, -C4-Salkyloxy, -C4-Sethioalkyl, -MH", and -M(C.4 -Svalkyl)", -MH(C.4-Svalkyl), -M-C(0)-(C4-Ce alkyl) or -MO"; - 50 KE. selected from H, halogen, -CM, -CHO, -CEz, -OSE", -"OH, -C4-Salkyl, -C4-Salkyloxy, -C4-Sethioalkyl, -MH", -MZ(C.4-Salkyl )», -M(С.--Svalkil), -М-С(0)-(С4-Svalkil), -МО», -М-С(0)-М(С.4-Szalkil)», - M-S(0)-MN(S.-Szalkil),

Co) -M-C(0)-0-(C4-Calkyl)», -502-C4-Calkyl, -5-C3-Cvcycloalkyl, -5-CH» C3-Ccycloalkyl, -3025-C3-Cvcycloalkyl, - 302-СН»2.C3-Св-cycloalkyl, -С3-Свcycloalkyl, -Сно-С3-Secycloalkyl, -О-С3-Secycloalkyl, -О-СНо-С3-Сеcycloalkyl, phenyl, benzyl, benzyloxy, morpholino or other heterocycles, such as pyrrolidine, piperidine, piperazine, furan, thiophene, imidazole, tetrazole, pyrazine, pyrazolone, pyrazole, imidazole, oxazole or isoxazole, and the cycles of each of these K,; groups are optional

IF) substituted by 1-3 substituents selected from the group H, halogen, -CM, -CHO, -SEz, -OH, -C4-Svalkylu, -C4-Svalkoxy, ime) -MH», -M(C--Svalkyl ), --MH(С--Svalkyl), -М-С(0)-(С4-Svalkyl), -MO", -505(С4-Svalkyl), -502МН(С4-Svalkyl), -5025(С4 -Szalkil)" or -OSE"; 60 or their pharmaceutically acceptable salt form.

It is to be understood that C.--Ceffluorinated alkyl groups in the definition of Ki can be any alkyl group containing from 1 to 6 carbon atoms with any number of fluorine substituents, including, but not limited to, -СЕз, alkyl chains containing from 1 to b carbon atoms, with a final trifluoromethyl group, -СРоСЕ з, etc. 65 Ester forms of these compounds include pharmaceutically acceptable ester forms known in the art, including forms that can be converted in the animal's body during metabolism into the free acid form, such as the free carboxyl form, for example, according to the invention, the corresponding alkyl esters can be used , cycloalkyl esters, aryl esters and their heterocyclic analogues, where alkyl esters, cycloalkyl esters and aryl esters are preferred, and alcohol residues may have additional substituents. Particularly preferred are C. and C. alkyl esters, preferably C. - alkyl esters, such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, isopentyl ester, neopentyl ester, hexyl ester, cyclopropyl ester, cyclopropyl methyl 7/0 ether, cyclobutyl ester, cyclopentyl ester, cyclohexyl ester, or aryl esters such as phenyl ester, benzyl ester or tolyl ester.

In the definition of X/, it is meant that the alkenyl bridging group -C-C- means the cis- or trans-orientation of the shown compound(s).

Pharmaceutically acceptable acid mimetic or mimetic compounds useful in the compounds of the present invention include compounds where Co is selected from the group: Tan che o -I Bema ia SCHI NI tv, Tv che) (acid mimetic compounds are shown attached to phenyl) where Ka is selected from -SEz, -CHz, phenyl or benzyl, and the phenyl or benzyl group is optionally substituted with 1-3 groups , selected from -C4-Salkyl, -Ci-Saloxy, -C4-Cithioalkyl, -C3, halogen, -OH or -COOH;

P is selected from -C3, -CH3, -"MnO, phenyl or benzyl, and the phenyl or benzyl group is optionally substituted by 1-3 groups selected from -C4-C6 alkyl, -C1-C6 alkyl, -C4-C4 thioalkyl, - CEz, halogen, -OH or -COOH; and r- selected from -СЕ»z or -С.4-Svalkilu. име) In the compounds according to this invention, its subgroups and intermediate compounds, the following are examples of variables: 60 Example K is -(СН2),-А, for example, where n is equal to 0 and/or A is a group sy y and also y she b5 t

J where B and C are as defined in this description.

Examples of each of B and C independently are unsubstituted phenyl, pyridinyl, pyrimidinyl, furyl, thienyl, or pyrrolyl groups, for example, where A is a group: y ? to what dk what how ve and k. -i K: A and: and I

Examples of K" are selected from H, halogen, -CM, -CHO, -SEz, -OH, -C4-Salkyl, -C4-Salkyloxy, -C4-Cylthioalkyl, -MH", 70. -M(C-Salkyl) ", -M(S.-Svalkil), -M-C(0)-(C4-Svalkil) and -MO".

Examples of K selected from H, halogen, -CM, -CHO, -CEz, -"OH, C.-Salkyl, -C1-Salkyloxy, -C.4-Cylthioalkyl, -MH", -M(C4-Salkyl) », -MH(C.-Svalkyl), -M-C(0)-(C4-Svalkyl), -MO», morpholino or other heterocycles, such as pyrrolidino, piperidine, piperazine, furan, thiophene, imidazole, tetrazole, pyrazine, pyrazolone, pyrazole, imidazole, oxazole and isoxazole.

In some variants, K»z and EC are implemented in practice. attached to the 5 and 6 positions of the indole ring.

An example of n" is 1.

Examples of X" are -O-, -505-, -MH- and -СНо-,

Examples of Be are groups selected from: and ok pieces of pu PEN y - ro: What o shi sho ee sm t and their m or pharmaceutically acceptable acid mimetic or mimetic compounds, where pu equals 0-2 and "

Kv and Ka are independently selected from H, halogen, -CM, -CHO, -SEz, -OH, -C.4-Cylalkyl, -C4-Cyloxy, -C4-Cylthioalkyl, -MH", -Ch(C.-Cylalkyl )", -MH(C4-Svalkyl), -M-C(0)-(C4-Svalkyl) or -MO". -

An example of pu is 0. m

In some embodiments, the -""CH 2)O 4 -CO 2 H group, or pharmaceutically acceptable acid mimetic or mimetic compounds are located at the 4-position of the phenyl ring.

Examples of n are the integers 1 or 2. Examples of po are 0, 1, or 2; for example, p. and both can be equal to 1. "

Xy, for example, can be selected from a chemical bond, -5-, -O-, -MH- or -Ш(S.-Szalkyl)-. -o : : y y y U U

Examples of Ki are C1-Salkyl, C3-Seccycloalkyl, phenyl, pyridinyl, naphthyl, tetrazole, each of which is optionally substituted with 1-3 substituents independently selected from H, halogen, -CM, -CHO, -SEz, - OSEz, -OH, :z» -S.-Svalkylu, -Si-Svalkoxy, -MNo, -M(S.--Svalkil)», -MH(S.--Svalkil), -M-C(0) -(S.-Svalkyl), -MO", -305(C4-Szalkyl), -502МН", -"502МН(С4-Szalkyl), -502М(С.4-Szalkyl)", -СООН, -СН. -СООН, -СНО-М(С.4-Svalkyl), -СНО-М(С.i-Svalkyl)», -СНо-МН»о, -С.4-Svthioalkyl, phenyl (additionally optionally substituted by halogens ), - 15 benzyloxy, -(C4-Calkyl)C(O)CH", -"C4-Calkyl)!OSN" and -C(O)MH".

In some variants of implementation in practice, Ki has the formula: -i "ВЕ из я | Shchi siv! - Pi m "z Bec de K»5, Kv and Ke are independently selected from H, halogen, -CM, -СНО, -СЕз, -ОСЕ", -ОН, -С4-Svalkylu, -С.-Svalkoxy, - MH", -M(S.-Svalkyl)", -MH(S.-Svalkyl), -M-C(О0)-(С4-Svalkyl) and -MO". 59 The first subgroup of compounds according to the present invention, or of their pharmaceutical salts, includes compounds

HF) of the above group, where A is a fragment: . ime) 60 schi Y and sho and B, C, p, p., po, Pz, pu, KE, X.4, Ho, Ku, Ko, Kz and KA are as defined above.

The second subgroup of compounds according to the present invention includes compounds of the above-mentioned first subgroup, where dev and C are unsubstituted phenyl, pyridinyl, pyrimidine, furyl, thienyl or pyrrolyl groups and b. Ho, Ko, Kz and Ku are as defined above.

The third subgroup of compounds and pharmaceutically acceptable salt forms according to the present invention includes compounds of the above-mentioned second subgroup, where A is a fragment: Kz and K. are as defined above. The fourth subgroup of compounds according to the present invention includes compounds of formulas (II) or (1): sha yava Ga 29 I o ! : rents of the present day "or - p. and? -I -I sh» - 50

Co.)

F) ime) 60 b5 zha che shi nn

B se shchi , i z yakya (5) de pich, po, Pz, Pa, X/, Ho, KK, Ko, Ez and EK. are as defined above or pharmaceutically acceptable salts thereof. m

The fifth subgroup of compounds according to the present invention includes compounds of formula (II) or (III), where p3-1, and p4, po, pu,

Hi, Ho, Kch, Ko, Kz and EK. are as defined above or pharmaceutically acceptable salts thereof. AND

The sixth subgroup of compounds according to the present invention includes compounds of the above-mentioned fifth subgroup, where Co is a phenyl substituted by a group of the formula -(СНо)м4-СО2Н, and optionally substituted by 1 or 2 additional substituents independently selected from H, halogen , -СМ, -СНО, -СЕз, -OH, -C4-Svalkylu, -S.-Svalkoxy, - -S.-Sethioalkyl, -MH», -M(C.4-Svalkyl)», -MH(С .-Svalkil), -M-C(0)-(S.-Svalkil) or -MO; and p4, po, pl, K.4, X., Xo, BK", Kz and K. are as defined above, or their pharmaceutically acceptable salts.

The seventh subgroup of compounds according to the present invention includes compounds of formulas (IM) or (M): «-c. and? -I -I sh» - 50

Co.)

F) name) 60 b5

Z shchi roya z st, Kin ih sajhi what de s 5 n chi y wich i sia g) vek . and don't eat anything

N - Kor r MAY v shcha I. m sna, she IY Ese NN. at 45

V y svi Y "I For the son of x y. Me too. and a :

Kn ay ik DE

Mnt vi i ro (e, і Shche R yy sh Y. tanya shcha still tia that | Ey o sh shhy AH zh Be -ya chn s

Kk: ШЯ ey k v o i, ih A nai

Jan: shchi Y "y sch or ich-r to them I same E ch - li, breath sya Z syu no still rek y V na Kil o It k what in

E N Mk inii I: her E z z

I'm a member of the U.S. Department of Education

SCHE ku: o svi ky SHY ESK « she Shi o, chrya yi K Bei ia y

What . I

ANN. WE, as well as Go -I s s tva AY "in a new way

E, sch y A zn ih Mono ШХ і ев я Хо 5

Ф) In Shshch-y ko ss. wa bo de: pi is an integer from 1 to 3; po is an integer from 1 to 3;

КБ, Кв and Ку independently selected from H, halogen, -СМ, -СНО, -СЕз, -ОСЕ», -ОН, -С4-Svalkylu, -"С4-Svalkoxy, -МН", -М(С1-Svalkyl) ", -"MN(S.-Svalkil), -M-C(0)-(S.-Svalkil) or -MO"; 65 Xy is selected from a chemical bond, -5-, -O-, -MH- or -M-(S.-Szalkyl)-;

X»o is selected from -O-, 50» or -CH»o-;

Ko represents a fragment selected from the group: я-и во че.

Kv and Ka are independently selected from H, halogen, -CM, -CHO, -SEz, -OH, -C.-Svalkyl, -Si-Svalkoxy, -MH", -M(C1-Svalkyl)", -"MH( S.-Svalkil), -M-С(0)-(S.-Svalkil) or -MO"; pa is equal to a whole number from 0 to 2;

Kz is selected from H, halogen, -CM, -CHO, -SEz, -OH, -C.Alkyl, -C4-Alkyloxy, -C.-Svetioalkyl, -MH", -M(C4-Alkyl)", MH( S.-Svalkil), -M-C(0)-(C4-Svalkil) or -MO"; and

K. selected from H, halogen, -CM, -CHO, -SEz, -OH, -C4-Salkyl, -C4-Salkyloxy, -C4-Cylthioalkyl, -MH", -M(C4-Salkyl)", - MH(C.-Svalkyl), -M-C(0)-(C4-Svalkyl), -MO", morpholino or other heterocycles, such as pyrrolidino, piperidine, piperazine, furan, thiophene, imidazole, tetrazole, pyrazine, pyrazolone , pyrazole, imidazole, oxazole or isoxazole; or pharmaceutically acceptable salt forms thereof. with

The eighth subgroup of compounds according to the present invention includes compounds of formulas (MI) or (MI): , where: o Xy is selected from a chemical bond, -5-, -O-, -MH- or -M-(S.-Szalkyl)-;

X»o is selected from -O-, -505- or -CH»o-; 60 Kz selected from H, halogen, -CM, -CHO, -CEz, -OH, -C4-Salkyl, -Ci-Salkyloxy, C.S-Sthioalkyl, -MH", -M(C1-Salkyl)", -MH (S.-Svalkil), -М-С(О0)-(S.-Svalkil) or -MO"; and

K; selected from H, halogen, -CM, -CHO, -SEz, -OH, -C4-Salkyl, -C--Salkyloxy, -C,4-Cylthioalkyl, -MH", -M(C4-Salkyl)", - MH(C.--Svalkyl), -M-C(0)-(C4-Svalkyl), -MO", morpholino or other heterocycles, such as pyrrolidino, piperidine, piperazine, furan, thiophene, imidazole, tetrazole, pyrazine, pyrazolone, pyrazole, imidazole, because oxazole or isoxazole;

pi is equal to a whole number from 1 to 2; po is equal to a whole number from 1 to 2;

КБ, Кв and Ку independently selected from H, halogen, -СМ, -СНО, -СЕз, -ОСЕ», -ОН, -С4-Svalkylu, -"С4-Svalkoxy, -МН", 500 7М(С1-Svalkyl) ", -MH(S.-Svalkil), -M-C(0)-(C4-Svalkil) or -MO";

Ka and K are independently selected from H, halogen, -CM, -CHO, -SEz, -OH, -C.-Svalkyl, -Si-Svalkoxy, -MH", -M(C1-Svalkyl)", -"MH( S.-Svalkil), -M-С(0)-(S.-Svalkil) or -MO"; or pharmaceutically acceptable salt forms thereof.

The ninth subgroup of compounds according to the present invention includes compounds of formulas (MI) or (MII), where p4 is 1; of 70 is 1 and X, Xo, Kz, Ka, K5, Kb, Ke and Ka and Ka are as defined in the eighth subgroup above, or their pharmaceutically acceptable salt forms.

The tenth subgroup of compounds according to the present invention includes compounds of the above ninth subgroup, where X 4 represents a chemical bond, n 4, po, Xo, Kz, Ka, K5, Kb, Ke and Ka and Ko are as defined in the above ninth subgroup, or their pharmaceutically acceptable salt forms.

The eleventh subgroup of compounds according to the present invention includes compounds of formulas (MI) or (IX) пп и диши шия сповысо Ки КО з0 и Ж но ча or "I aty в Pk -I oven where:

Sh- ; ; ; . pi is equal to a whole number from 1 to Z; r» po is equal to 0;

Chi is a chemical bond; - and shi - . . pz, Pa, Ho, KU, Ko, E.z and KV. are as defined above or pharmaceutically acceptable salts thereof. that) The twelfth subgroup of compounds according to the present invention includes compounds of formulas (X) or (XI)

F) name) because b5

- gu And her where.

M I school "SN lreeni av v y z ; She is xx and there is

Ж and Ш brought out (hi or y izhy zo i a them

Kn it k s. "! show no m where: pi is equal to a whole number from 1 to Z; - po is equal to 0;

КБ, Кв and Ку independently selected from H, halogen, -СМ, -СНО, -СЕз, -ОСЕ», -ОН, -С4-Svalkylu, -"С4-Svalkoxy, -МН", -М(С1-Svalkyl) ", -"MN(S.-Svalkil), -M-C(0)-(S.-Svalkil) or -MO"; "

Chi is a chemical bond; X» is selected from -O-, -505- or -CH»o-;

EC" is a fragment selected from the group: - ; R. and works whose 5: s eSoo . I. with -2.I married I en iy s with I. in i ) 5 y

Ka and K are independently selected from H, halogen, -CM, -CHO, -SEz, -OH, -S.-Svalkylu, -Si-Svalkyl, -MH», 22 -M(S.-Svalkyl)», -MH (C1-Svalkyl), -M-C(0)-(C4-Svalkyl) or -MO";

ГФ) pa is equal to a whole number from 0 to 2;

Kz is selected from H, halogen, -CM, -CHO, -CEz, -OH, -C4-Swalkyl, -C--Swallowoxy, -C.4-Swthioalkyl, -MH», where -M(S4-Swalkyl)2 , -Щ(С.--Svalkil), -М-С(0)-(С.4-Svalkil) or -MO"; and

K; selected from H, halogen, -CM, -CHO, -SEz, -OH, -C4-Cylalkyl, -C--Cyloxy, -C.4-Cylthioalkyl, -MH», 60 -M(C.Cylalkyl)» , -MH(C.-Svalkyl), -M-C(0)-(C4-Svalkyl), -MO", morpholino or other heterocycles, such as pyrrolidino, piperidine, piperazine, furan, thiophene, imidazole, tetrazole, pyrazine , pyrazolone, pyrazole, imidazole, oxazole or isoxazole; or pharmaceutically acceptable salt forms thereof.

The thirteenth subgroup of compounds according to the present invention includes compounds of formulas (XIII) or (ХП): b5

I-Y with Z and EE in I as

Yes, yes, yes. WE" and already about

WHAT, what, what, and what; » change yourself nn oh sleepy, where

YOU tai Yani zay o-t OD iya She iy shk Se shany Z ay h y

Zh sen: Y tu tiy is Zh sn Y

M Ziya pe; -0- Ba "in i and

KE y y yar, SHO y-y times other with zv Me o shiy she

Red gkyyanehh z Y t a son ey Kovoyaee i ka no be p en sche B zea o kis VY She. -- V y" "Mn saze I zam She knows she zey ekusa is svy a but y. I -- "7 pa She s o z o z y i - « where:

Chi is a chemical bond; what

X»o is selected from -O-, -505- or -CH»o-; m

Kz is selected from H, halogen, -CM, -CHO, -CEz, -OH, -C4-Swalkyl, -C--Swallowoxy, -C.4-Swthioalkyl, -MH", -M(C1-Swalkyl)", -MH(S.-Svalkyl), -M-C(0)-(C4-Svalkyl) or -MO"; and

K; selected from H, halogen, -CM, -CHO, -SEz, -OH, -C4-Salkyl, -C--Salkyloxy, -C,4-Cylthioalkyl, -MH", -M(C4-Salkyl)", - MH(C.--Svalkyl), -M-C(0)-(C4-Svalkyl), -MO", morpholino or other heterocycles, such as "du pyrrolidino, piperidine, piperazine, furan, thiophene, imidazole, tetrazole, pyrazine, pyrazolone, pyrazole, imidazole, with oxazole or isoxazole; c pi is equal to a whole number from 1 to 2; :z" po is equal to 0;

KB, Kv and Ku are independently selected from H, halogen, -CM, -CHO, -SEz, -OSE", -OH, -C4-Svalkylu, -"C4-Svalkoxy, -MH", 15 -M(C1-Svalkyl )», -МН(С.-Svalkil), -М-С(0)-(С4-Svalkil) or -MO»; - Ka and K are independently selected from H, halogen, -CM, -CHO, -SEz, -OH, -S.-Svalkyl, -Si-Svalkoxy, -MH", -M(C1-Svalkyl)", -"MH (S.-Svalkil), -М-С(0)-(S.-Svalkil) or -MO"; - and or their pharmaceutically acceptable salt forms. The compounds of the invention can be used to treat, suppress, relieve or alleviate asthma and asthmatic conditions. Methods of treating, suppressing, alleviating or alleviating asthma and asthmatic conditions according to the present invention include methods of treating acquired bronchial asthma (also known as allergic asthma or atopic asthma), hereditary bronchial asthma (also known as non-allergic asthma or non-atopic bronchial asthma ) or combinations thereof, termed mixed asthma.Conditions in patients experiencing or being affected by acquired or allergic asthma include those caused by or associated with multiple allergens such as pollen, spores, grass or weeds, house dander animals, dust, mites, etc. Due to the fact that allergens and other irritants themselves are present at different times throughout the year, these

HF) types of cases are also called seasonal asthma. The group of acquired asthma also includes bronchial asthma and 7 allergic aspergillosis of the bronchi and lungs.

Hereditary bronchial asthma, which can be treated or relieved by these methods, includes cases caused by infectious agents such as cold and flu pathogens in adults and respiratory syncytial virus (RSV), rhinovirus and influenza virus common in children. Also included are asthmatic conditions that can be triggered in some asthmatics by exercise and/or cold air. The methods are applicable to inherited asthma associated with industrial or occupational exposures such as smog, ozone, noxious gases, sulfur dioxide, nitrogen oxide, fumes including isocyanates, fumes of paint, plastics, polyurethanes, varnishes, etc. ., wood, plant dust or other organic dust, etc. The methods are also applicable for asthmatic cases associated with food additives, preservatives and pharmacological preparations. Common substances of these types are food dyes such as tartrazine, preservatives similar to bisulfites and metabisulfites, and pharmacological agents such as aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs).

Also included are methods of treating, suppressing, or alleviating types of asthma called latent asthma or cough-like asthma.

The methods described herein are also applicable to the treatment or alleviation of hereditary bronchial asthma associated with gastroesophageal reflux (GERD), which can stimulate bronchial stenosis. SECO, along with retained secretions, suppressed coughs, and exposure to allergens and irritants in the bedroom, can contribute to asthmatic conditions called nocturnal asthma or Mosiigpa! asthma In methods of treating, inhibiting, or alleviating asthma associated with SECO, a pharmaceutically effective amount of a compound of the present invention can be used as described herein in combination with a pharmaceutically effective amount of a drug to treat SECO. These drugs include, but are not limited to, proton pump inhibitors, similar to pantoprazole sodium extended-release tablets of the trademark RKOTOMIHF), omeprazole capsules of prolonged action of the trademark RKIOBESFYA, rebeprazole sodium /5 tablets of the extended-release trademark ASIRNEHO, or lansoprazole capsules of prolonged action of the trademark

RECEMASIOF). It is clear that pharmaceutically effective amounts of these drugs include amounts described in conventional medical literature, including pharmaceutically effective doses and methods of use of these drugs, described in 2001 Rpuzisiapz OezK Keiegepse (55 Ethiopia), Medisa! Esopotisv Sotrapu, MopimaIe, Mem

Ouegzeu 07645-1742.

The compounds and methods of the present invention are useful for treating, ameliorating, suppressing and ameliorating arthritic conditions in mammals. Methods of the present invention include alleviating, inhibiting, ameliorating and treating in mammals arthritic conditions including, but not limited to, rheumatoid arthritis, spondyloarthropathy, gouty arthritis, infectious arthritis, osteoarthritis (which includes erosive osteoarthritis and also known as osteoarthritis or degenerative arthrosis or 000), systemic lupus erythematosus and Steele's disease. Each of these methods includes administering to a mammal, as needed, a pharmaceutically effective amount of a substituted indole according to the invention as described herein, or its i) pharmaceutically acceptable salt or ester form.

Methods of the present invention include methods of treating arthritic conditions associated with spondylitis, including ankylosing spondylitis, reactive arthritis (Reiter's syndrome), psoriatic arthritis, arthritis associated with chronic inflammatory bowel disease, and AIDS-related seronegative spondyloarthropathy. -

The present invention also provides methods of treating, alleviating or suppressing rheumatic diseases and "E disorders. These methods are applicable for the treatment of systemic lupus erythematosus, systemic sclerosis and forms of scleroderma, polymyositis, dermatomyositis, necrotizing vasculitis and other vasculopathies, hypersensitivity vasculitis (including Schönlein-Henoch disease), Wegener's granulomatosis, giant cell arteritis, and mucocutaneous lymphatic syndrome (Kawasaki disease), Behçet's syndrome, cryoglobulinemia, juvenile dermatomyositis, Sjogren's syndrome, overlapping syndromes (including mixed diffuse connective tissue disease), polymyalgia rheumatica, erythema nodosum, relapsing polychondria, tendonitis (tenosynovitis), biceps tendonitis bursitis, ulnar bursitis, adhesive capsulitis of the shoulder (scapulohumeral periarthritis), spring fingers, and Whipple's disease. Compounds of the present invention are also useful for treating, ameliorating, or inhibiting metabolic or endocrine diseases with rheumatic conditions, including gout, pseudogout, chondrocalcinosis, amyloidosis, scurvy, specific conditions of enzyme deficiency (including Fabry disease, alkaptonuria, ochronosis, Lesch-Nyhan syndrome and Gaucher disease), hyperlipoproteinemia (types II, Pa, IM), syndrome

Ehlers-Danlos, Marfan syndrome, elastic pseudoxanthoma, Wilson's disease. In addition, rheumatic conditions associated with endocrine diseases, such as diabetes, acromegaly, hyperparathyroidism, ossifying progressive myositis, hypermobility syndrome, congenital complex arthrogryposis, and thyroid diseases such as goiter, thyroiditis can be treated with these methods. and Based's disease. These methods can also be used in rheumatic conditions associated with neoplasms, such as a primary tumor (synovioma), metastatic tumors, multiple myeloma, leukemia and lymphoma, pigmented villonodular synovitis, osteochondromatosis, and others. The methods according to the present invention also include relief from rheumatic diseases

With conditions associated with neuropathic disorders, including Charcot joints, hand tremor syndrome (also known as vibration-induced white finger syndrome or Raynaud's syndrome), repetitive stress syndromes, sympathetic reflex dystrophy, and compressive neuropathies such as peripheral neuropathy (Including carpal tendon syndrome, pronator syndrome, superior aperture syndrome and tarsal tunnel syndrome), radiculopathy and spinal canal narrowing. (F) The compounds and methods of the present invention are useful for treating, alleviating, and suppressing the conditions, pain, and inflammation associated with them. Methods of treating, alleviating, suppressing or ameliorating these conditions in a mammal include administering to the mammal, in need of such activity, a pharmaceutically effective amount of a compound according to the present invention, alone or in combination with another drug, such as an anti-rheumatic, anti-inflammatory or analgesic pharmaceutical.

A further method of treating asthma according to the present invention comprises administering to a mammal in need of such treatment a pharmaceutically effective amount of a compound according to the present invention as described above and a pharmaceutically effective amount of one or more additional anti-asthma drugs. 65 Antiasthmatic drugs applicable with these combinations include long-acting medical drugs such as corticosteroids (glucocorticoids), cromolyn sodium (disubstituted sodium cromoglycate - OSS),

nedocromil, methylxanthines (such as theophylline), and leukotriene modifiers. Applicable leukotriene modifiers include leukotriene receptor antagonists such as zafirlukast (ASSOCIATE F) and monetlukast (ZIMSSHI AIIKF)), and 5-lipoxygenase inhibitors such as zileuton (UR OF)). Applicable corticosteroids include inhaled products such as beclomethasone dipropionate, budesonide, flunisolide, fluticasone, and triamcinolone, as well as their pharmaceutically acceptable salt forms. Systemic corticosteroids such as prednisone, prednisone, and methylprednisolone are also applicable.

Also applicable are fast-acting anti-asthmatic medications such as long-acting beta-agonists, short-acting beta-agonists, anticholinergics and systemic corticosteroids, p-adrenergic agents that 7/0 Can be used include epinephrine, isoproterenol, metaproterenol, terbutaline, isoetarin , albuterol, bitolterol, and perbuterol. Applicable anticholinergic agents include atropine (and its derivative ipatropium bromide) and glycopyrrolate. Compounds of the present invention can also be used to treat asthma in conjunction with allergy immunotherapy, often referred to as hyposensitization therapy. These compounds can be administered according to doses and requirements known in the art.

Additional antiasthmatic drugs that may be used in combination with this invention include pranlukast, anakinra, seratodast, olopatadine hydrochloride, lisethyl cromoglycate, ramatroban, interleukin-4 receptor (immunex), urodilatin, colforsin daropat, salbutamol, 1!SV-2183, andolast , ciclesonide, budesonide, formoterol, omalizumab, tranilast, saredutant, СОР-835 (apii-II-5 Mab), fexofenadine

NS, M-(1-(chlorophenyl)-1-methylethyl)-3-(imidazol-1-yl)upropylamine dihydrochloride (875-71-321), cilomilast, bimosiamos, corticotropin-releasing factor, clenoliximab, tiotropium bromide, 2H -1,2-benzoselenazine,

3,4-dihydro-4,4-dimethyl (VHT-51072), atreleuton, (K)-salbutamol, 8-methoxyquinoline-5-(M-(2,5-dichloropyridin-3-yl)y)carboxamide (0 -4418), triamcinolone acetonide, / KMUu-4490 (KE-19514), GAH-300 (Х-109), IPES-152 (5T-152; antn-СО-23 antibody), cytokine Tharz, anandamide, ZKI-172 , salmeterol k fluticasone, KSA-757, 2-pyridinecarboxylic acid, su 8-(2-(3,4-diethoxyphenyl)-4-thiazolyl)-(ORS-6535), PrzeM-5609, salbutamol, St-2820 (inhibitors ROEM), beclomethasone, nepadutant, ketotifen fumarate, ONEA5 (RV-005), Rpagtargo|esiv Mo5163, Mo5278 and Mo5297, o salbutamol sulfate, ERI-2010 (Erisepkh), mepolizumab, benzamide,

IM-(5-(3-(4-chlorophenyl)sulfonyl)propyl)-2-(1H-tetrazol-5-ylmethoxy)phenyl)-3-((4-(1,1-dimethylethyl)-2-thiazolyl) m ethoxy)-, monosubstituted sodium salt (UM-158), with 2-(4-ethoxycarbonylaminobenzyl)-6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyrazin-3-one. RIagtargo)|esiv (Mo5450),

Zsp-205528, I-826141 (Ripapgtargo)esiv Mo5477), budesonide, duramycin, sodium salt of 4,4-bis(4-(quinolin-2-ylmethoxy)phenyl)pentanoic acid (MMI-530), inhibitor of 1- 9, beclomethasone dipropionate, formoterol, cyclo(MeRNe-I ep-Avzr-MaI-O-Aga-O-Aga) (20-7349), salbutamol, ethanaminium, 2-((2-acetyl-4-(( 1-oxohexadecyl)amino)phenoxy)hydroxyphosphinyl)oxy)-M,M,M-trimethyl-, inner salt - (СРЕ-2015), РО-168787 (СИ-1018), cathepsin 5 inhibitors, 5В-240683 (apii- /-4 MabB), VII -284, ARS-2059, Kk. budesonide and formoterol, Vau-16-9996 (antagonist 1/-4), beclomethasone, SMUuU-328267, Mi A-4 antagonists, 4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H) -quinolinone (TA-270), SrO-7909 (RgoMipe), OMK-Z3ZZA (Rpaptargo|eziz Mob070), AMUO-12-281, I M-1507 (1M-1484), formoterol, MOI -6131, cathepsin 5 inhibitors ,

C5-615, ibudilast, 2-(M-(4--4-chlorophenylsulfonylamino)butyl)-M-13-(2-(4-cyclobutylthiazol-2-yl)ethyl)" benzyl)sulfamoyl)benzoic acid (5- 36527) and EB with 2-(IM-(4--4-chlorophenylsulfonylamino)butyl)-M-73-(4-isopropylthiazol-2-yl)umethyloxy) and benzyl)sulfamoyl)benzoic acid (5-36496). "" The present invention also includes pharmaceutical compositions comprising a pharmaceutically effective amount of a compound according to the present invention, or a pharmaceutically acceptable salt form thereof, and one or more pharmaceutically acceptable carriers or excipients. -i Compounds according to the present invention can be used in a pharmaceutical composition when they are combined with a pharmaceutically acceptable carrier. Such a composition may also contain (in addition to the compound or compounds - according to the present invention and the carrier) diluents, fillers, salts, buffer solutions, stabilizers, substances that increase solubility, and other substances well known in the art. The term "pharmaceutically acceptable" means a non-toxic substance that does not interfere with the biological activity of the active ingredient(s). and Media characteristics will depend on the method of administration. 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 the side effects caused by the compound of the present invention.

The pharmaceutical composition according to the invention can be in the form of a liposome, in which the compounds according to the present invention are combined, in addition to other pharmaceutically acceptable carriers, with amphipathic agents, iF) such as lipids that exist in an aggregated form in the form of micelles, insoluble monolayers, liquid crystals or co-lamellar layers in an aqueous solution. Suitable lipids for liposomal formulations include, but are not limited to, monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponins, bile acids, and similar compounds. The preparation of such liposome formulations is known in the art and is described, for example, in US Pat

No. 4,235,871, U.S. Patent No. 4,501,728, U.S. Patent No. 4,837,028, and U.S. Patent No. 4,737,323, each of which is incorporated herein by reference.

As used herein, the terms "pharmaceutically effective amount" or "therapeutically effective amount" refer to the total amount of each active component of a pharmaceutical composition or method that is sufficient to show significant benefit to a patient, i.e., to treat, cure, prevent, inhibit, or ameliorate a physiological response or condition. , such as an inflammatory condition or pain, or to increase the rate of treatment, healing, prevention, inhibition or amelioration of such conditions. When applied to an individual active ingredient administered alone, the term refers to that single ingredient.

When applied to a combination, the term refers to the combined amounts of the active ingredients resulting in a therapeutic effect, regardless of whether they are administered in combination, sequentially, or simultaneously.

Each of the methods of treatment or use of the present invention described herein includes administering to a mammal, in need of such treatment, or using a pharmaceutically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof. Compounds according to 7/0 of the present invention can be administered by the method according to the invention alone or in combination with other therapy, such as treatment using other anti-inflammatory drugs, cytokines, lymphokines or other hematopoietic factors.

When co-administered with one or more other anti-inflammatory drugs, cytokines, lymphokines or other hematopoietic factors, the compounds of the present invention can be administered simultaneously with other anti-inflammatory drug(s), cytokine(s), lymphokine(s), by other(s)/5 Hematopoietic factor(s), thrombolytic or antithrombotic agents, or sequentially. With sequential administration, the attending physician will decide the appropriate sequence of administration of the compounds according to the present invention in combination with other anti-inflammatory drug(s), cytokine(s), lymphokine(s), other hematopoietic factor(s). amy), thrombolytic or antithrombotic agents.

Administration of the compounds of the present invention in a pharmaceutical composition or for the practice of the method of the present invention can be accomplished by a variety of conventional routes, such as oral administration, inhalation, or by dermal, subcutaneous, or intravenous injection.

When a therapeutically effective amount of the compounds of the present invention is administered orally, the compounds of the present invention will be in the form of a tablet, capsule, powder, solution, or elixir. When administered in tablet form, the pharmaceutical composition according to the invention may additionally contain a solid carrier such as gelatin or an adjuvant. The tablet, capsule and powder contain from about 5 to 9595 compounds of the present invention and preferably from about 25 to 9095 compounds of the present invention. When administered in liquid form, a liquid carrier such as water, petroleum, animal or vegetable oils such as peanut oil, mineral oil, phospholipids, emulsifiers, triglycerides including medium chain triglycerides, soybean oil or sesame oil may be added. or synthetic oils. The liquid form of the pharmaceutical composition may additionally contain a physiological saline solution, a solution of dextrose or another saccharide, or glycols such as ethylene glycol, propylene glycol or polyethylene glycol. When administered in liquid form, the pharmaceutical composition contains approximately 0.5 to 909 omas. compounds according to the present invention and, preferably, from about 1 to 5095 compounds according to the present invention.

When a therapeutically effective amount of the compounds of the present invention is administered by intravenous, dermal or subcutaneous injection, the compounds of the present invention will be in the form of a pyrogenic, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable protein solutions having the appropriate pH value, isotonicity, stability, etc., is known in the art. A preferred pharmaceutical composition for intravenous, dermal or subcutaneous injection should contain, in addition to the compounds of the present invention, an isotonic diluent such as sodium chloride injection solution, injection solution "

Ringer's solution for injection, dextrose solution for injection, dextrose and sodium chloride solution for injection, lactate injection (/- with Ringer's solution, or other solvent known from the state of the art. The pharmaceutical composition according to the present invention may also contain stabilizers, preservatives, buffer substances, or antioxidants, other impurities, known to a specialist in this field.

The amount of compound(s) of the present invention in a pharmaceutical composition of the present invention will depend on the nature and severity of the condition to be treated and the nature of the prior treatment to which the patient has been subjected. Ultimately, the attending physician will decide the amount of compound of the present invention to treat each individual patient. Initially, the attending physician will administer low doses of the compound of the present invention and observe the patient's response. More substantial doses of the compounds of the present invention can be administered until the patient's optimal therapeutic effect is obtained, at which point the dosage is not further increased. It is assumed that various pharmaceutical compositions used for the practical implementation of the method according to the present invention should contain

He from about 0.1 µg to 100 mg (preferably from about 0.1 mg to B50 mg, more preferably from about 1 mg to 2 mg) of the compound according to the present invention per kg of body weight.

The duration of intravenous therapy using the composition according to the present invention will vary depending on the severity of the disease to be treated, the condition and potential characteristic reaction of each individual patient. It is believed that the duration of each administration of the compounds according to this (F) invention will be in the range of 12 to 24 hours of continuous intravenous administration. Ultimately, the attending physician will decide on the appropriate duration of intravenous therapy using a pharmaceutical composition according to the present invention. in Preferred oral lipid-based formulations of the present invention are prepared by mixing 5095

РНОБЗОГ О5З3МСТ (Атегисап И есиип Sotrapu), 59о Роиузогра(е 80, 1595 glycerides (АВКАЗОЙ ZSarguIosargoui tasgodo!-8 (Sacetozze Sogr.), 1590 propylene carbonate and 1595 active inhibiting sRI A» compound(s) according to this invention, and each the percentage listed below is by mass.

The present invention also offers a method for preparing compounds according to the present invention, which includes one of the following: a) reaction of a compound of formula A with

Vk. Ha

Me, woman I, Z ER Shk sha chenie 10 KE I her de X", p, p., Po, Pz, Pa, K, Ko, Ez and Ku, are as defined in this description; and K' is MH", with a sulfonyl halide of the formula halogen-ZO5(CHNo)poX A, where halogen is a suitable halogen and n", X and Ku are as defined herein, leading to 72 obtaining the corresponding compound of the formula (I), or

B) hydrolysis of a compound of formula (I), where Co includes an ester, leading to the corresponding acid, or c) conversion of a compound of formula I having a reactive substituent into another compound of formula I, or 20 4) reaction of a compound of formula A ve K i

Mo c 25 t, 7 she, and Y 30 where Ho, p, pl, Po, Pz, Pa, K, Ko, Kz and K. are as defined in this description; and M

B" represents -МН-5(0)25-(СНо)по-halogen or -МН-5(0)5-СНАСН» and po is as defined in this description, with a nucleophile of the formula: М

NK, - where H. and Ku. are as defined herein, leading to the corresponding compound of formula (1); 35 or - e) alkylation of the compound of the formula

В , 40 ОО an вх З "» where K, Ku, KU, Ku, Hu. and po are as defined in this description, an aldehyde or an acetal of the formula "He Y ve t or bu jako t , 45 i: Shk a ru She nn Shan. - where Co", Ho" and pz are as defined in this description, or iz 7) the reaction of Z-formylindole of the formula 50 and a'

ОВ Е ka where RKT is a protecting group, K, K 4 , Kz, Ku, Hu and po are as defined herein, with an amine of the formula: in KiNM-СНо-К», where Ku is hydrogen or C 4-Alkyl and Co is as defined in this description, leading to the preparation of a compound of formula I, where Xo represents -K;;M-CH»o-, or 9) the reaction of an alkylamine of formula b5

Z , I and dech are separate: y chi gyi se ut shiya where halogen is a suitable halogen and K, K» and K. are as defined in this description, with an alkyne of the formula o not and where Ku, Ko, Hu and Ho are as defined in this description, leading to a compound of the formula (I) or n) the reaction of a halide of the formula and

Ve --Щ Her U en vij shi her a

Which de de halogen is a suitable halogen and K, K», Kz, Ka, Xo, pi and pz are as defined herein, with a sulfonamide of the formula ns sere Be | see

Noah kn 5 Ge) she - de Ku, Hu. and po are as defined in this description, leading to the corresponding compound of formula ()X.

The present invention also provides intermediate compounds useful for the preparation of compounds of formula (I), and these intermediate compounds include compounds having the formula (A): M a - -:. NV No | r an z i shy Reshaik hv ssh in "di. -at

Z de Ho, p, pl, Po, Pz, Pa, K, Ko, Kz and K. are as defined above; and :z" B" is selected from the group consisting of -OH, -MH-5(O) o-(CHO)po-halogen, -MH-5(0)5-SNACH»o, -MHo or a protected form - MN".

Intermediate compounds that are examples have the formula (B):

With oh

E:shchy Her ia " r y over M Ж, also і vi (F; where p, pl, Po, Pz, Pl, K, Ko, Kz and K. are as defined above; and

GI Ka and Co are independently selected from H, halogen, -CM, -CHO, -SEz, -OSEz, -OH, -C S.-Swalalkyl, -S.-Swalkoxy, -S.-Sestioalkyl, -MH", - M(C.4-Svalkil)", -MH(S.-Svalkil), -M-C(0)-(S.4-Svalkil) or -MO"; in K, is - (СН 2)4-СОоН, an ester form of -(СНо)4-СОоН or a pharmaceutically acceptable acid mimic or mimetic compound; and

X is a binding group selected from the group consisting of -O-, -CH»-, -505-, -MH- and -(S.-Svalkyl)-.

A preferred variant of intermediate compounds according to the present invention includes benzhydrindole compounds 65 of formula (C):

k- sa; t : chi zyshe Yae HER soda vk za iv z di: I W I ate s. ZHI KB them vyt nvvty still I and. Yan" uran B veins Y

KE I. sia o pd 70 che u pevud i g Best y chi shva a u yabm, lu --

So; WE where:

B, Kz, Ku, K7.o, X, p, Po and pd are as defined above; and

Ko, Kulya, Ki», Kz, Kid and K/5 are independently selected from the group consisting of H, halogen, -CM, -CHO, -CE z, -OCE»5, -OH, -C4-Svalkylu, - С--Svalkoxy, -МН», -М(С4-Svalkyl)», -МН(С.-Svalkyl), -М-С(О0)-(С4-Svalkyl), -MO» or 5- or b- -len heterocyclic or heteroaromatic ring containing 1 or 2 heteroatoms selected from O, M or 5.

The term "halogen" is used in this description to denote E, SI, Bg and I. The predominant halogen atoms are B! ch group -MH-5(0)5-(СНо)п»-halogen include bromine and chlorine. Gee)

Preferred ester forms of compounds of the formula C, where K is -(СН 2)м4-СО2Н, are

C.-Svalky esters, including linear, branched and cyclic alkyl groups, and benzyl esters.

Available commercially and known from the state of the art protecting groups for the amino group are used to obtain the protected forms of the above-described -(СНо)й4-МНо groups. These protecting groups include groups represented by the following formulas, where the number of carbon atoms in the chain is provided for illustrative purposes only and is not intended to limit the number of carbon atoms in the corresponding carbon chains according to the present invention. M zu y -

Zo mia a NN ra. B. shiZ yes in. with M M Z sa. b: Shi Mopa M

I am | - in: also g. Z V. as 2 S o i « 5 o) . y I I BE y I De no t same To l-y

I am A

Other non-limiting examples of amino protecting groups applicable to the compounds of the invention include, but are not limited to, the following compounds: 1) of the amide type, such as formyl, acetyl, chloroacetyl, trichloroacetyl, o-nitrophenylacetyl , - o-nitrophenoxyacetyl, trifluoroacetyl, acetoacetyl, phthalyl and p-toluenesulfonyl;

Kz 2) aromatic carbamate type, such as benzyloxycarbonyl (CB2) and benzyl substituted one or more times by alkyl, cyano, nitro, chlorine, fluorine, bromine and methoxy; diphenylmethyl, 1-(p-diphenyl)-1-methylethyl, 9-fluorenylmethyl (Etos), 2-phenylethyl and cinnamyl groups;

C) aliphatic carbamate type, such as tert-butyloxycarbonyl (Bos), ethyl, diisopropylmethyl, allyl, vinyl, tert-amyl, diisopropylmethyl and isobutyl; (F) 4) cyclic alkyl carbamate type, such as cyclopentyl, cyclohexyl, cyclopropylmethyl and g adamantyl; 5) protective groups of the alkyl type for the amino group, such as triphenylmethyl (trityl) and benzyl; in 6) trialkylsilane groups, such as trimethylsilane, triethylsilane, triisopropylsilane, tri-tert-butylsilane, triphenylsilane, tritolylsilane, trimesitylsilane, methyldiphenylsilane, dinaphthylmethylsilane, bisidiphenyl)methylsilane, etc.; and 7) thiol-containing protecting groups such as phenylthiocarbonyl and dithiasuccinoyl protecting groups.

Other preferred amino protecting groups useful in the present invention are 65 ethoxycarbonyl groups, acyl groups including 4-chlorobutyryl, isobutyryl, o-nitrocinnamoyl, picolinoyl, acylisothiocyanate, aminocaproyl, benzoyl and the like, and acyloxy groups including methoxycarbonyl,

9-fluorenylmethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 1,1-dimethylpropynyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl and the like.

Pharmaceutically acceptable acid mimetic or mimetic compounds that can be attached at the K7 position include compounds of the formulas: a. zr z ee ay s V z vesni zuskrnny OK ANNA. a KN oi m - y sto: NN par z tn sovno s: shchi 7170 5 ih Zh. -K. and I am me

C) SL sie S, still ij She v giv i se

B Su "ryu: and and SHE ve and dolav shi: in de or Ж nav i" I na renny І A se i sche she E SCHE I E zh zi a I ish

And I | E ikh ey oy ven ay po i ssh shi shi SHA. a or, o p na ee o a p m shk What zi

The ring - du de Ca is selected from -C3, -CH3, phenyl or benzyl, and the phenyl or benzyl groups are optionally substituted by 1-3 groups selected from -C.4-Salkyl, -C--Salkyloxy , -C4-Sethioalkyl, -SEz, halogen, -OH or -COOH; c K is selected from -СЕ3, -СН3, -МНо, phenyl or benzyl, and the phenyl or benzyl groups are optionally substituted by 1-3 groups selected from -С.4-Salkyl, -С--Svaloxy, - C4-Sethioalkyl, -SEz, halogen, -OH or -COOH; and Ks is selected from -SEz or -S.-Svalkilu. 15 Another preferred variant of the compounds according to the present invention is represented by the formula 0:

Not y: o 7 where each of the variables Kz, Ku, Ka-Kchv, X and pa are as defined above. Compounds of formula (0) in which K/0o-K4i5 are hydrogen are particularly preferred. Another preferred variant of the intermediate compounds according to the invention are compounds of the formula E b5 t5 where each of the variables Ku3-K.»5 and X are as defined above.

A particularly preferred embodiment of this invention in practice are compounds of formula E, in which

Kio-Kiv5 are hydrogen.

Among the most preferred intermediate compounds according to the present invention are the following compounds, named intermediate compounds Mo 1, 2 and 3. An illustrative method of obtaining these 20 compounds is also shown. These examples of particularly preferred compounds and methods should not be construed as limiting the scope of the invention.

The preparation of intermediate compounds is illustrated below:

Intermediate compound Mo1

4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3Z-ylylethanesulfonyl)benzoic acid methyl ester

Stage 1: 2-Bromo-4-chloroaniline (1.00 equiv.) is dissolved in CH 2Si" (025M), then triethylamine and trifluoroacetic anhydride (1.1 equiv. each) are added. The resulting mixture is stirred at 35 room temperature for 1 hour. Then the solvent is removed from the reaction mixture and the residue is purified - by flash chromatography with dichloromethane as an eluent, obtaining the desired product with a yield of 9790. t/2 (М-Н)- 300.0.

Step 2: M-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroacetamide (Step 1, 1.Oeq.) is mixed with 3-butyn-1-ol (2.Eq.), dichlorobis (triphenylphosphine)palladium(I!) (2.5Uoeq.), triethylamine (3.Oeq.), Si! (5bOseq.) in DMF - (0.2M) in a hermetic vessel in an atmosphere of Mo and heated at 12092 for 4 hours. Then the reaction mixture is diluted with ethyl acetate, washed with a saturated salt solution and dried over Ma 2503. Next, the solvent is evaporated and the residue is purified by column flash chromatography using a mixture of 290 Meon/SnH Si, obtaining the described 2-(5-chloro-1H -indol-2-yl)ethanol with a yield of 67905. t/2 (M-H) 194.09. 45 Stage 3: 0 2-(5-chloro-1H-indol-2-yl)ethanol (Eq.) is added to a solution (under M 2) containing -I tert-butyldiphenylchlorosilane (1.2 eq.), imidazole ( 2, beq.) and DMF (1.8M). The reaction mixture is stirred overnight. Quench with ManNSO" (aq.) and extract with a mixture of EBO/EUAc. The organic layer is washed with water, saturated salt solution and dried over sodium sulfate. They are purified on a column with silica gel and their mixture 1:4 hexane/SnCl is used as an eluent. /2-(C-tert-butyl(idiphenyl)silyl|oxy)ethyl)-5-chloro-1H-indole (yellow oily substance) is obtained with a yield of 9890. - Stage 4: To a solution containing 2-(C-tert-butyl( diphenyl)silyl|oxy)ethyl)-5-chloro-1H-indole (Tech.), TFO

GI (Eq.) and 1,2-dichloroethane (0.1 M), methyl 4-((2-oxoethyl)sulfanyl|benzoate (3.7 eq.) is added at 09С under a Mo atmosphere. Then EBb5iH (12 eq.) is added, the reaction mixture is allowed to warm to room temperature and stirred overnight. The reaction mixture is quenched with Manceau (aq), extracted with EtOAc, washed with brine, and dried over sodium sulfate. Purified on a silica gel column, and a 1:5 mixture of EtOAc is used as the eluent /hexane. Methyl (F, 4-(12-(2-(2-tert-butyl(idiphenyl)silyl|oxyethyl)-5-chloro-1H-indol-3-yl|ethyl)sulfanyl)benzoate is obtained (solid yellow ka substance) with an output of 79905.

Stage 5: To a suspension of Man (1.1 equiv) in DMF (0.37M) at 0 9C in an atmosphere of Mo, add methyl in 0 4-Ch2-(12-(2-Itret-butyl(idiphenyl)silyl|oxy)ethyl )-5-chloro-1H-indole-3-yl|ethyl)isosulfanyl)benzoate / (Tech.). Minutes later, RP2SNVHg (1.8 eq.) is added and the reaction mixture is warmed to room temperature. After 3 hours, the reaction mixture is quenched with MHCl (aq.), extracted with a mixture of EtOAc/EBO, washed with water, saturated salt solution and dried over sodium sulfate. It is purified on a column with silica gel and a 1:5 EtOAc/hexane mixture is used as an eluent. Methyl vB 0 3-YD-(42-(1-benzhydryl-2-(2-tert-butyldiphenyl)silyl|oxy)ethyl)-5-chloro-1H-indol-3-yl|ethyl)sulfanyl)phenyl| Benzoate (a yellow resinous substance) with a yield of 6590.

Step 6: To a solution/suspension containing methyl 3-14-(42-(1-benzhydryl-2-(2-tert-butyldiphenyl)silyl|oxy)ethyl)-5-chloro-1H-indol-3-yl |iethylsulfanyl)phenyl|benzoate (Eq.), acrylonitrile (0.1 M) and molecular sieves (1 g/mmol benzoate) under Mo add MMO (4 eq.).

After 10 minutes, TRAP (0.12 eq.) was added and the mixture was heated to 402C. After 1.5 hours, the reaction mixture is cooled, filtered and the filtrate is collected. Purified on a silica gel column using a 1:5 mixture

EtOAc/hexane. Methyl 3-14-(42-(1-benzhydryl-2-(2-tert-butyldiphenyl)silyl|oxy)ethyl)-5-chloro-1H-indole-3-yl|ethylsulfonyl)phenyl|benzoate (solid) is obtained white substance) with a yield of 7190. 70 Stage t. To the solution methyl 3-I4-(42-(1-benzhydryl-2-(2-tert-butyldiphenyl)silyl|oxy)ethyl)-5-chloro-1H-indol- Tetrabutylammonium fluoride (1M in THF) (1.2 eq.) is added to 3-ylethylsulfonyl)phenylbenzoate (Eq.) and THF (0.1M) at 092C in a Mo atmosphere.

The reaction mixture is heated to room temperature and after 1 hour quenched with MN SI (aq). They extract

EtOAc, washed with saturated salt solution and dried over sodium sulfate. It is purified on a column with 75 silica gel using a mixture of 1:9 ЕЯАС/СН 2Си». Methyl 3-14-(12-(/1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-ylethyl)sulfonyl)phenyl|benzoate (white solid) was obtained in a yield of 8690.

Stage 8: To a solution of methyl 3-I4-(42-(/1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl|ethylsulfonyl)phenyl|benzoate (Teq.) in

СНоси" (0.05 M) at 092С in a Mo atmosphere add СНзЗОС"-СИ (2 eq.) and EBM (2.5 eq.). After 1 hour, the reaction mixture is heated to room temperature. After an additional hour, water is added and CH Si is extracted, washed with saturated salt solution and dried over sodium sulfate. Remove the solvent to give methyl 3-(4-4C2-(1-benzhydryl-5-chloro-2-2-(methylsulfonyl)oxy|ethyl)-1H-indole-3-ylethyl|sulfonyl)phenyl)benzoate Ge (solid light yellow substance) with a yield of 9995. o

Stage 9: Methyl 3-(4-4C2-(1-benzhydryl-5-chloro-2-2-(methylsulfonyl)oxy|ethyl)-1H-indole-3-ylethyl|sulfonyl)phenyl)benzoate (Tech.), sodium azide (bq.) and DMF (0.05M) are mixed in an atmosphere of Mo and heated to 602. After 1 hour, the reaction mixture is cooled and water is added. It is extracted with a mixture of E(AcC/ESO), washed with water, a saturated sodium chloride solution and dried over sodium sulfate. The solvent is removed, obtaining methyl m 3-I4-(42-(2-(2-azidoethyl)-1-benzhydryl-5 -chloro-1H-indole-3-ylethylusulfonyl)phenyl|benzoate (solid light yellow substance) with a yield of 99905. "I

Stage 10: Methyl 3-I4-(12-(2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indole-3-ylethylusulfonyl)phenyl|benzoate m (1 eq.), PPRNiz (2 eq.) and THF (0.1 M) were mixed under Mo and stirred overnight. Water (1 mL/immol benzoate) was added and the reaction mixture was again stirred overnight. The solution was concentrated and purified on a silica gel column using a 3:11 mixture of E(OAc /hexane, followed by 5906 MeOH in СНоСі". Methyl 3-I4-(12-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|igthyl)sulfonyl)phenyl is obtained |Ibenzoate (a light yellow solid) with a yield of 99905. «

Synthesis of an intermediate My! also described below in Example 135, steps 1-8. This intermediate can also be synthesized by method K or method M, explained below. - с Intermediate compound Мо2 h» Methyl ether of 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-ilyethoxy)benzoic acid pyridiyt»

Kz Stage 1: To the methyl ester of 4-hydroxybenzoic acid (1.0 equiv) in DMF (0.83M) is added K.»cSoO»z (2.Eq.), followed by the addition of 2-bromo-1,1-diethoxyethane and the reaction mixture is stirred at 1102 for 2 days.

TLC shows a new spot. The reaction mixture is diluted with ethyl acetate, washed with Tn Mahon, water, saturated saline solution, dried over sodium sulfate and the solvent is removed, obtaining the desired product with a yield of 84905. This substance is used in the next step without additional purification. (F) Stage 2: To a mixture of the product obtained in the previous stage (1.0 eq.) and 5-chloro-2-methylindole (1.Eq.) in

Triethylsilane (3,Eq.) is added to ГСНоСИБ (0.12M), followed by the addition of trifluoroacetic acid (3,Eq.).

After stirring overnight at room temperature, water and trifluoroacetic acid (Teq.) are added to the reaction mixture, stirred at room temperature for 2 days, diluted with CHCl, washed with In Mason, water, saturated salt solution and dried over sodium sulfate. Trituration of the substance in a mixture of СНоСи» and hexane gives N3 alkylated indole with a yield of 92965.

Stage 3: To the indole from the previous stage (1.0 eq.) in DMF (0.36 M) at 259C, ManN (1.2 eq., 6bO9o dispersion in oil) is added and the brown solution is stirred at a temperature from 0 to -5 "C for 1 hour, then 65 bromodiphenylmethane (1 equiv) was added and the reaction mixture was stirred overnight, then quenched with water, diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate, and purified by column chromatography to give the desired product in the yield 72965.

Stage 4: To M-alkylated indole from the previous stage (1.0 equiv.) in SSI; (0.2M) add M-bromosuccinimide (2.Eq.) and a catalytic amount of benzoyl peroxide. The solution is boiled under reflux

According to it, cool to 252C, filter and wash the solid substance with SSI/. The filtrate is concentrated to a foam, which is dried. The foam is dissolved in acetone and NaCl (1.Eq.) is added, after which water is added and the reaction mixture is stirred overnight 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 brine, dried over sodium sulfate, and then chromatographic purification of the residue gives 7/0 the desired product in a yield of 8595. Alternatively, the dibromide from the reaction with M-bromosuccinimide can be poured into

DdMSO (10-2095 concentration by mass), stirring for 30 minutes at room temperature. After completion of the reaction, the reaction mixture is poured into water and the precipitate obtained as a result is separated by filtration, the precipitate on the filter is washed with water and dried, obtaining essentially a quantitative yield.

Stage 5: Ammonium acetate (4 eq.) is added to the aldehyde from the previous stage (1.0 eq.) in CH with 3MO" (0.2 M) and 7/5 of the resulting mixture is refluxed for 4 hours. Then, the reaction mixture is diluted with EtOAc and washed with a saturated salt solution. The aqueous phase is extracted with E(Ac. The combined organic phases are washed with saturated salt solution, dried over sodium sulfate, and concentrated until a solid yellow-hot crystalline substance is precipitated. The mixture is cooled overnight and the nitroolefin is collected by filtration (yield 7696). Evaporation of the solvent phase and purification of the residue with a column chromatography (gradient elution 20 10095 toluene-»195 EtOAc-toluene) gives an additional amount of nitroolefin (yield 23905).

Stage 6: Zinc dust (20 equiv.) is suspended in 595 aqueous solution of NSI (8M 2p/595 NS). Nasi is added to this mixture" (0.2 century). The mixture is shaken for 10 min, the aqueous phase is decanted and replaced with fresh 5905 NOSI, the mixture is shaken again for 2 min. and the aqueous phase is removed. Then the zinc-mercury amalgam obtained in this way is added to a mixture of nitroolefin (1.0 equiv.) and concentrated NS! (8Eq.;) in THF (004M su 25 Nitroolefin/THF). The mixture is brought to a gentle boil under reflux for 1 hour. Product formation is monitored by TLC. The mixture is cooled to room temperature and the solid is removed by filtration through celite. Concentrated MH OH is added to the solution phase and the mixture is concentrated on a rotary evaporator. The residue is dissolved in CH 5Si" and concentrated MNAOH. The aqueous phase is extracted

СН»оСИ» and the organic phase are washed with saturated salt solution, dried over sodium sulfate and concentrated. su 30 Purification by column chromatography gave the desired product (yield 6590).

The synthesis of intermediate compound Mo2 is also described in example 1, stages 1-6. This intermediate can also be synthesized using methods K, I, or M, as outlined below. "

Intermediate compound MoZ

Methyl ether of 4-13-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|Ipropyl)/benzoic acid - with echin svy 40 ki i o) s Stage 1: A mixture of methyl-4-iodobenzoate (5.3m, 20.2mmol), allyl alcohol (1.78g, 30, 3mmol), Manso with :z" (4.24g, 50.5mmol), RY(OAc)' (0 ,14g, 0.bOmmol), (n-Vy)AMVg (6.55g, 20.2mmol) and molecular sieves 4-A (41g) in anhydrous DMF (b39ml) were stirred at room temperature for 4 days. The reaction mixture is filtered through celite, the filtrate is poured into water and extracted with EIUAs. The organic layer is washed with a saturated solution of -1 salt, dried (Ma»5O)) and concentrated in vacuo. Flash chromatography (silica gel, 10-2095 E(Ac-hexane)) afforded 2.11 g (8595 based on reduced starting material) of the desired 4-(3-oxopropyl)benzoic acid methyl ester as a clear oily substance. : TFO (1, 78g, 15.mmol), after which triethylsilane (1.81g, 15.mmol) is added. The reaction mixture is stirred overnight, quenched with a saturated solution

KZ Manso" (5 Oml) and the organic layer are washed with saturated solution of Manso", water, saturated salt solution and dried (Ma»5O)). The solvent was removed under reduced pressure and the residue was purified by flash column chromatography using a mixture of 10-2095 EAs/hexane to give the desired product in a yield of 59496 (1.67g).

Stage C: To a solution of the product obtained in stage 2 (1.66g, 4.8bmmol) in DMF (20ml) is added Mann (6095 in (F) mineral oil, 0.24g, 5.83mmol) under Mo atmosphere. The mixture is stirred for 1 hour at room temperature

He temperature, after which benzhydryl bromide (1.8g, 7.29mmol) in DMF (5ml) was added dropwise. This reaction mixture is stirred overnight at room temperature. Water (500 ml) is added to the reaction mixture, it is extracted with EtOAc, washed with a saturated salt solution, dried (Ma»SO)) and concentrated under reduced pressure to a brown syrup, which is purified by chromatography on silica gel using a mixture of 1095

EtOAc/hexanes as eluent to give 4 as a white solid in a yield of 5995 (1.47g).

Stage 4: The product from the previous stage (1.46g, 2.87mmol) is dissolved in SSI; (14.5 ml), after which it is added

M-bromosuccinimide (1.02 g, 5.7 mmol) and benzoyl peroxide (2 mg). The reaction mixture is boiled with reflux in a refrigerator for 1 hour (until all the starting substance disappears). This mixture is cooled to room temperature, filtered, and the solid is washed with sodium chloride. The filtrate is evaporated to a brown residue, which is dissolved in acetone (40 ml) and water (4 ml), then AdoSoO (1.75 g, 3.1 mmol) is added to this solution, and after stirring overnight at room temperature, the solution is filtered through celite, the solvent is evaporated under reduced pressure and water is added to the residue. This mixture is extracted with EUDAs, washed with saturated /Solution of salt, dried (Ma»zoO),) and evaporated to a syrup, which is purified with a mixture of 1095 E(Ac/hexanes, isolating 2-formylindole (1.13 g) with a yield of 7595. Alternatively, dibromide from reactions with M-bromosuccinimide can be poured into

DMSO (10-2095 concentration by weight) and stir for 30 minutes at room temperature. After completion of the reaction, the reaction mixture is poured into water and the precipitate obtained as a result is separated by filtration, the precipitate on the filter is washed with water and dried, obtaining essentially a quantitative yield. 70 Stage 5: MNAOAc (0.077g, Tmmol) is added to the solution of 2-formylindol from the previous stage (0.52g, Tmmol) in SNUMO" (6.2ml), the mixture is refluxed for 1 hour, then NH is added /OAc (0.077 g, 1 mmol), continue to reflux for an additional 1 hour, add MNAOAc (0.077 g, Tmmol) again and continue heating for an additional 1 hour. The reaction mixture is cooled to room temperature, E(Ac (50 ml) is added, after which 100 ml of water is added. The aqueous layer is extracted with EtOAc 5! the combined organic layers are washed with a saturated salt solution, dried (Ma»5O)) and evaporated until a yellow foam is formed , which is subjected to chromatographic purification, using a mixture of 1090 E(UAc/hexanes as eluent, obtaining 6 in the form of a yellow foam with a yield of 6895 (0.38G).

Stage b: Get 2p(Noah) by adding NosSi! o (34g, 7.2mmol) to a mixture of zinc dust (34.68Hg, 530.35mmol) and 595 NSI (Zvml) in a 100ml flask and intensively stirring this mixture for 1 hour. The aqueous phase is decanted, Zvml 595 NSI is added again and the mixture is stirred for 1 hour. The aqueous phase is decanted. This solid was added to vinyl nitro compound 6 (15g, 26.57mmol) in THF (bbOml) and concentrated NH (64.5ml). This mixture is stirred at room temperature for 1 hour, then refluxed for 15 minutes. The reaction mixture is cooled to room temperature and filtered through Celite. An aqueous solution of MH.OH (200 ml) is added to the filtrate and stirred for 15 min. and remove THF under reduced pressure. The aqueous layer is extracted with CH 2Si", the combined organic layer is washed with a saturated salt solution, dried (Ma»3O),) and concentrated to a brown foam, which is purified by column chromatography, i) first eluting the column with CHCl3 to remove non-polar impurities, then with a mixture of 295 Meon/sney with to isolate the desired amine in a yield of 46595 (6.1g).

The synthesis of intermediate MeoZ is also described below in Example 42, steps 1-6. This intermediate can also be prepared using methods .), K, or M as outlined below.

Intermediate compound Mo4 -

Methyl ether of 4-12-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-ylethylamino) benzoic acid "g

Stage 1: To a solution of 4-chloro-2-iodaniline (16.5g, 65.1mmol) in DMF (250ml) at room temperature for 70 hours, add o-bromodiphenylmethane (21.5g, 84.mmol) and zoRGOMEI (23ml, 130mmol ) and the reaction mixture is heated at 8 s 459 overnight. After removal of volatile substances under reduced pressure, the residue is dissolved in E(UAc, washed with water (Zh), saturated salt solution and dried over MazO). Purification by column chromatography on 5IO" (from hexanes to a mixture of 595 EAs/hexanes) gave the desired benzhydryl-(4-chloro-2-iodophenyl)amine (26.1 g, yield 97905) as a yellowish solid. -1 75 Stage 2: A mixture of benzhydryl-(4-chloro-2-iodophenyl)amine (26.1g, 62.2mmol), Rasi (PP) (1.90g, 2.67mmol),

Si! (1.2g, b.2mmol), Z-butyn-1-ol and EBM (120ml) are stirred at 4592 for 20 hours. The reaction mixture is filtered through Celite and washed with EtOAc. The filtrate is concentrated, redissolved in E(As), washed with water (3x) and a saturated salt solution and dried over Mazo,. Crude 4-(2-(benzhydrylamino)-5-chlorophenyl|but-3-yn-1-ol (25.5 g) is used at the next stage directly without additional purification.

Kz Stage 3: A solution of crude 4-(2-(benzhydrylamino)-5-chlorophenyl|but-3-yn-1-ol (25.5g) and Si! (2.7g, 14.1mmol) in DMF (200ml) heated at 1259 for 24 hours. The reaction mixture was filtered through celite and washed with E(Ac. The filtrate was concentrated, redissolved in E(Ac, washed with water (3x), saturated saline solution and dried over Mao5O,. Column chromatography on silica gel (3096 E(OAc/hexanes) afforded the desired 2-(1-benzhydryl-5-chloro-1H-indol-2-yl)ethanol as a yellow solid (14.5g, 7395 over 2 steps).(F) Step 4: Imidazole (3.72 g, 55, 0 mmol) and TVORBZSI (13.2 ml, 50.6 mmol). After stirring at the same temperature for 1.5 hours, the reaction mixture was washed with cold water (3x), saturated salt solution and dried over Mozo. The crude silyl ether was used directly for the next stage without additional purification.

Stage 5: Add oxalyl chloride (4.84ml, 55.5mmol) dropwise to a solution of crude silyl ether in EO (200ml) at 09Сb. The reaction mixture is allowed to warm to room temperature and stirring is continued for 4 hours, after which EC 3M (Zbml) and Meon (1Oml) are added. The mixture is washed with water, b5 saturated salt solution and dried over Mao5O). Crude ketoester is directly used in the next stage.

Stage 6: To the keto ether in THF (300ml) dropwise at room temperature is added VN z.Me»5 (100M, Zbml) and the reaction mixture is refluxed overnight. The mixture is cooled to 0 2C, after which Mmaon (3090, 150ml) is added and stirring is continued for 30 minutes. Under reduced pressure, THF is removed, the reaction mixture is extracted with E(As), washed with water, a saturated salt solution and dried over Mo5oO.

Purification by column chromatography (a mixture of 15 to 2095 EIAs/hexane) gave the desired product as a white solid (15.9g, 24.7mmol, 5895 for stage 3).

Stage 7: Add dropwise to a solution of oxalyl chloride (0.372 ml, 4.27 mmol) in CH-SiO (1 Oml) at -7892C

DMSO (0.661 ml, 9.3 mmol). The reaction mixture is stirred at the same temperature for 5 minutes, after which a solution of 2-(11-benzhydryl-2-(2-(tert-butyldiphenylsilanyloxy)ethyl|-5-chloro-1H-indol-3-yl)ethanol ( 2.50 g,

Z, 8v8mmol) in СНоСиИ» (Vml). After additional 40 min. After stirring, IROMEI (3.38 ml, 19.4 mmol) is added, the reaction mixture is quenched with cold water (bml) and extracted with CHCl. The organic layer is dried over Mo50O and evaporated. Crude 11-benzhydryl-2-(2-(tert-butyldiphenylsilanyloxy)ethyl|-5-chloro-1H-indol-3-ilyacetaldehyde 75 is used directly in the next stage.

Stage 8: Methyl 4-aminobenzoate (645mg, 4.27mmol), acetic acid (1.3ml) and Mavn(OAc) are added to a solution of crude aldehyde (3.88mmol) in 1,2-dichloroethane (30ml) at 09С. The reaction mixture is allowed to warm to room temperature overnight and is quenched with cold ManNSO. Extractive treatment gives the desired methyl ester 20 of 4-(2-71-benzhydryl-2-(2-(tert-butyldiphenylsilanyloxy)ethyl|-5-chloro-1H-indol-3-yl)ethylamino)benzoic acid, which is directly used for the next stage without additional purification.

Step 9: To 4-(2-711-benzhydryl-2-(2-(tert-butyldiphenylsilanyloxy)ethyl|-5-chloro-1H-indol-3-yl)ethylamino)benzoic acid methyl ester (3.8v8mmol) in To THF (25 ml) at 09C, a mixture of HOAc1M TVAE (in THF) (2.3ml:5.3ml) is added and the reaction mixture CM 25 is stirred at room temperature for 18 hours. Extractive treatment followed by trituration in d) of a 590 EtOAc/hexane mixture gives the desired 4-2-11-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl|stylamino)benzoic acid methyl ester acid, with a small admixture, in the form of a solid, off-white substance (9295 according to the C stage).

Stage 10: To a solution of methyl ether with 30 d-42-(1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-ylylethylamino)benzoic acid (1.64g, C, 04mmol) in M

СНоСИ" at 09С add EBM (0.63 bml, 4.5 bmmol) and Massey (0.282 ml, 3.b4mmol). After stirring at the same temperature for 35 min. the reaction mixture is quenched with cold water. Extractive treatment gives crude Z mesylate as a solid off-white substance (1.7Og, 90905). Cha

Step 11: A solution of crude mesylate (1.70g, 2.75mmol) and Mam z (89mg, 13.dmmol) in DMF (14ml) was stirred at 802C for 6 hours. The reaction mixture is diluted with EtOAc and treated with water, followed by flash column chromatography, obtaining the desired methyl ester 4-2-(2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-ylethylamino) of benzoic acid (81 Zmg, yield 52905).

Stage 12: To a solution of 4-(2-(2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethylamino)benzoic acid methyl ether (400mg, 0.709mmol) in THF RPzR (223 mg, 0.851 mmol) was added portionwise to T0 (ml) at 09 C. The reaction mixture was stirred at room temperature for 11 hours and at 3523 for 4 hours, after which water (5 µM) was added and stirring was continued overnight. The reaction mixture is diluted with EtOAc, dried with Mo95O, and purified by flash column chromatography (from EtOAc to 2095 Meon/EAc with 195 EBM), obtaining the desired methyl ester 4-2-(2-(2-aminoethyl)-1-benzhydryl-5 -chloro-1H-indol-3-ylethylamino)benzoic acid (201mg, 5390) in the form of -1 solid.

The synthesis of intermediate Mo4 is also described below in example 142, steps 1-12. - and Intermediate compound Мо5 их Methyl ether of 4-(12-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethyl)methylamino)benzoic acid -.720 HO

Already B a o Stage 1: Crude 11-benzhydryl-2-(2-(tert-butyldiphenylsilanyloxy)ethyl|-5-chloro-1H-indole-3-ilyacetaldehyde from the synthesis of intermediate compound Mo4, stage 7 is treated with methyl ether 4 -methylaminobenzoic acid by the procedure described in the synthesis of intermediate Mo4, step 8, to give the desired methyl ester bo 4-(2-(1-benzhydryl-2-(2-(tert-butyldiphenylsilanyloxy)ethyl|-5-chloro-1H-indole) -3-yl)lethyl)methylamino|benzoic acid with a yield of 73905.

Step 2: The title compound was prepared by the procedure described for Intermediate Mo4, Step 9. Crude 4-(12-(/1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indole-3) methyl ester -ilyuethyl)methylamino)benzoic acid directly 65 is used in the next stage without additional purification.

Stages 3-6: Methyl Ether

4-(12-(2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ylethylmethylamino)benzoic acid was prepared by the procedure described for intermediate Mo4, stage 10-12 in yield 6195 (according to stage C).

Stage t. Solution of 4-(12-(2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethylmethylamino)benzoic acid methyl ester (410 mg,

0.709mmol) and 1095 Pa/C (155mg) in MeOH:CHNOCl (7ml:"ml) are stirred under an atmosphere of NO (Tatm) for 2 hours 15 minutes. The reaction mixture is filtered through celite and washed with Meon and SNCl." Flash column chromatography of the residue (from CsHnCIb to 890 mM) gives the desired methyl ester of 4-((2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-ylphenylmethylamino)benzoic acid with a yield of 7890 7 /0.(Vo5mg).

The synthesis of intermediate Mo5 is also described below in example 146, steps 1-7.

Compounds according to the present invention can be used as intermediate compounds in the synthesis of pharmaceutically applicable compounds of formula I, including compounds having formula IA: g and ; don't go to MD know and " same U; sec tenty

Nini: I'm sorry

Sha A) with 30 where:

X represents a connecting group selected from -O-, -CH»-, -505-, -MH- and -Щ(S.-Svalkil)-; -

Ko, Kch4, Ku", Kiz, K44 and Kiv are independently selected from H, halogen, -СМ, -СНО, -СЕз, -ОСЕ»з, -OH, -S.-Svalkylu, "g -S.-Svalkoxy, -MH», -M(C.--Svalkyl)», -MH(C.4-Svalkyl), -M-C(0)-(C4-Svalkyl), -MO» or 5- or b-membered heterocyclic or a heteroaromatic ring containing 1 or 2 heteroatoms selected from O, M or 5; і- 35 Ka and Ko are independently selected from H, halogen, -СМ, -СНО, -СЕз, -ОСЕз, -ОН, -С4-Салкылу, -С4-Салкоксы, и- -С.-Sestioalkyl, -МН» -M(C.4-Svalkyl)", -МН(С.-Svalkyl), -М-С(0)-(С.4-Svalkyl) or -MO";

K, is a compound of the formula -(CH 2 ) O 4 -CO 2 H or a pharmaceutically acceptable acid mimetic or mimetic compound, as defined above;

ER" and K are as defined above; "40 pi is equal to the whole number from 1 to Z; c to is equal to a whole number from 0 to 4; . Xy is selected from a chemical bond, -5-, -O-, -5X0)-, -5X0)2-, -МН-, -МНО(О)-, -С50О, sh: 45 Jak ; and ey -i "Ve v , or e i - n, 1

Ko) zh i- AN zh i a o, t van Y I Her I. i o x 1 vo m y

Kv is a cyclic group selected from C 1-Svalkyl, C-Sffluorinated alkyl, C3-Seocycloalkyl, tetrahydropyranyl, camphoryl adamantyl, CM, -M(C.--Svalkyl)", phenyl, pyridinyl, pyrimidinyl, furyl, thienyl, naphthyl, morpholinyl, triazolyl, pyrazolyl, piperidinyl, pyrrolidinyl, imidazolyl, piperazinyl, thiazolidinyl, thiomorpholinyl, 65 tetrazole, indole, benzoxazole, benzofuran, imidazolidin-2-thione, 7,7-dimethylbicyclo|2.2.1)heptan-2-one or a pyrrolyl group, each of which is optionally substituted by 1-3,

preferably, 1-2 substituents independently selected from H, halogen, -CM, -CHO, -SEz, -OH, -C.-Svalkyl, -C1-Svalkyl, -MH», -M(C.4-Svalkyl) », -MH(C.-Svalkyl), -M-C(0)-(C4-Svalkyl), -MO», -505(C4-Svalkyl), -502МН»5, -502МН(С4-Svalkyl), -50254(C.4-Svalkyl)", -OSEz, -"СООН, -СН.-СООН, -СНО-М(С4-Svalkyl), -СНо-М(С.-Svalkyl)", -Сно-МН », pyridine or 70 penya bezhanya pish 18 i oh NYA KI Ziya and Z shi nn no i or their pharmaceutically acceptable salt or ester forms.

Among the more preferred ester forms of compounds of the formula (IA), where K7 has the formula -(СНо)па-СО2Н, there are C 4-Svalalkyl esters, which include linear, branched or cyclic alkyl groups or c benzyl esters. at

The compounds of the invention may be prepared by any of the methods described herein. Where necessary, reactive moieties or sites during the reaction can be protected with suitable protective reagents, which are removed after the reaction is complete. Suitable reagents are well known in the art.

Compounds of the formula I can be prepared by a method involving the interaction of a compound of the formula A, where K' is MH", with a sulfonyl halide of the formula hapogen-505 (СНо)п»Х1Ви, where the halogen is a suitable M halogen, for example CI, and Hu. and K. are as defined in this description. This can be done accordingly under two-phase conditions, for example, using a mixture of aqueous sodium bicarbonate/dichloromethane, or in an organic solvent with the addition of a blocked organic amine base. M

Compounds of the formula | can also be prepared by a method involving the hydrolysis of a compound of formula I wherein Co 32 includes an ester to give the corresponding acid. This can be done under basic conditions - sodium hydroxide in water, methanol and THF at room temperature or at elevated temperature.

An alternative cleavage can accordingly be carried out by treatment with sodium thiomethoxide in a solvent such as THF or DMF at elevated temperature (eg 5020-1002). "

Compounds of formula I! can also be prepared by a process involving the conversion of a compound of formula I, which has a reactive substituent, into another compound of formula I. For example, a halogen can be converted to a non)c corresponding amine. This can be conveniently accomplished using a base, an amine, a phosphine ligand, and a palladium reagent. Compounds of formula I can also be prepared by a process involving the interaction of a compound of formula A, wherein is -MH-5(0) 2-(СНо)po-halogen or -МН-5(0)2СНАСН". and po is as defined in this description, with a nucleophile of the formula НХ.К., where X. and K. are as defined in this description. This can be done accordingly,

using a suitable organic base, such as Nypidv base, and heating until the reaction is complete. -I Compounds of formula I can also be prepared by a method that includes alkylation of a compound of formula i:

GI where K, Ku, KU, Ku, Hu. and po are, as defined herein, an aldehyde or acetal of formula b. o or b o ' even k ni sk ni de K", X" and pz are as defined in this description. This can be conveniently accomplished with Brønsted or Lewis acids such as trifluoroacetic acid and a reducing agent such as triethylsilane.

Compounds of formula I, where Xo is -K iiM-СНо-, can be prepared by a method that includes the interaction

C-formylindole of formula b5

0-5 , ee and s In sa shu with lei I o io, nt, Still Shsteni

I. Where RKT is a protecting group, K, K 4 , Kz, Ku, Hu, and po are as defined in this description, with an amine of the formula -K;iNM-CH» -Ko-, where K; ;, represents hydrogen or S.-Szalkil and Co. is as defined herein.

This procedure can accordingly be carried out in a mixture of a reducing agent such as sodium triacetoxyborohydride and an acid such as glacial acetic acid. Suitable protecting groups are well known in the art.

Compounds of formula I can also be prepared by a process involving the interaction of an alkylamine of the formula on NN I and Y i and wherein halogen is a suitable halogen, for example, I or Bg, and K, K»z and K are as defined herein , with an alkyne of the formula , et and - also where Ki, Ka», Hu. and Xo are as defined herein. with

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

Compounds of formula I can also be prepared by a process involving the interaction of a halide of formula

would

F 9

WE sote seam M shk and the essence o. where halogen is a suitable halogen, for example, Bg, and K, K", Kz, Ku, X" and pz are as defined in this description, with a sulfonamide of the formula ts de Ku, Hu and po are as defined in this description. "» This procedure can be carried out accordingly, using a strong base, such as Mann, n-butyl, etc.

The present invention can be further explained by the following non-limiting specific examples that illustrate the preparation of the compounds according to the invention. -I Method A -i sh» -i

Ko) ime) 60 b5

For: zrsu yak i SE sia She VO Z. V aTsanh y yav y gg A g (- se in Her . a hat eni same ee Esh tai I oromeuvnynimik : S oh y sho ind ES CHET a. taz ti ALL sho scan ng: PI - OH I AND my nen

Be On rya other s ZhK a YASNO in Z do shere Mav, Yashevon and I and Ka MYZh nn Esh ok ih My vyy ve En ia NV y I zvy

Let me drink it and let me drink it

Cl iy Ey y "Eh y y;

In Z v i and ES in B i

5 more months of ЖЖ ОО зенвавчийтийс: в- ко. ZY Mne KVN ge sr about water be; sleep DE SHY M si NN 6 Shk Mr. NN, cha ha « deenai i shi ek y i -

MON Y u re Vyaya pai: I: re x sshshe

In I o)

Method A iv. and . and - and?" The starting indole of method A can be alkylated in the NW position (carbon atom in the C-position of the indole group) with aldehydes or appropriate acetals in the presence of a Lewis or Brønsted acid, such as boron trifluoride etherate or trifluoroacetic acid. The indole nitrogen can then be alkylated by treatment with a strong -I base such as sodium bis(trimethylsilyl)amide, n-butyl-II, sodium hydride, or potassium hydride in a solvent such as DMF, DMSO, or THF, followed by reaction with the appropriate alkyl halide. The resulting product can be treated with carbon tetrabromide in carbon tetrachloride and a catalytic amount of benzoyl peroxide to effect dibromination of the C2 metal group. Then the dibromide can be mixed with silver carbonate in a mixture of acetone and water for 5 minutes, or poured into DMSO and mixed. Both data - procedures give an aldehyde, which is then subjected to a nitroaldol reaction with nitromethane and a catalytic amount of

He of ammonium acetate under reflux. The intermediate vinyl nitro compound obtained as a result is reduced to the amine by treatment with zinc-mercury amalgam in a mixture of THF and concentrated NSI under reflux. This amine can then be treated with the necessary sulfonyl chloride under two-phase conditions, in an aqueous solution of sodium bicarbonate/dichloromethane, or in an organic solvent with the addition of a blocked organic amine base. The final hydrolysis is carried out with the main ones

F) conditions with sodium hydroxide in water, methanol and THF at room temperature or at elevated temperature. ka Alternative cleavage can be accomplished by treatment with sodium thiomethoxide in a solvent such as THF or

DMF, at elevated temperature (50202-10022). This method is used in the syntheses of examples 1-88, 108-112 and 126-128.

Method В - KV innocence in the same ZO o shi sa i: ek io dn ss got dne y I iona st say i: Z ditya as sr tsi sk r -gy bo

The method

The starting halide of method B is refluxed in an aqueous solution of sodium sulfite and a suitable cosolvent, if necessary, such as alcohol, dioxane, etc., for the required time to obtain the desired sodium sulfonate. This intermediate compound is treated with thionyl chloride, pentachloride or phosphorus oxalyl chloride in dichloromethane with a small amount of DMF and stirred for several hours at room temperature to obtain the sulfonyl chloride. The sulfonyl chloride obtained in this way is then used crudely in method A. This method is used in the synthesis of examples 1-88, 108-112 and 126-128, when the sulfonyl chloride is not commercially available. 70 Example 1: 4-(2-(1-benzhydryl-2-2-((benzylsulfonyl)amino|ethyl)-5-chloro-1H-indol-3-yl)ethoxy|benzoic acid

This synthesis is described in method A.

Stage 1: To the methyl ester of 4-hydroxybenzoic acid (1.0 equiv) in DMF (0.83M) is added K.»cSoO»z (2.Eq.), followed by the addition of 2-bromo-1,1-diethoxyethane and the reaction mixture is stirred at 1102 for 2 days. 7/5 TLC shows a new spot. The reaction mixture is diluted with ethyl acetate, washed with 1 N Fat, water and saturated salt solution, dried over sodium sulfate and the solvent is removed, obtaining the desired product with a yield of 8495. This material is used in the next step without additional purification.

Stage 2: Triethylsilane (33.Eq.) is added to the product from the previous stage (1.Eq.) and 5-chloro-2-methylindole (1.Eq.) in SNSO" (0.12M), followed by the addition of trifluoroacetate acid (3Z, Equiv.). After stirring overnight at room temperature, water and trifluoroacetic acid (1.0 eq.) are added to the reaction mixture, stirred at room temperature for two days, diluted with SiOCl, washed with sodium hydroxide, water, saturated salt solution and dried over sodium sulfate. Trituration of the substance in a mixture of СНоСи» and hexanes gives

NW alkylated indole with a yield of 9295.

Stage 3: To the indole from the previous stage (1.0 eq.) in DMF (0.36 M) at 259C, Mann (1.2 eq., 6090 s dispersion in oil) is added and the brown solution is stirred at a temperature from 0 to -592C for 1 hours, then bromodiphenylmethane compound (1.1 eq.) is added and the reaction mixture is then stirred overnight. It is then quenched with water, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and purified by column chromatography to give the desired product in 7290 yield.

Stage 4: To the M-alkylated indole from the previous stage (1.0 eq.) in SSI, (0.2 M) add M-bromosuccinimide CM (2. eq.) and a catalytic amount of benzoyl peroxide. The solution is refluxed for 3 hours, cooled to 252C, filtered, and the solid is washed with HCl. The filtrate is concentrated to foam, which is dried. The foam is dissolved in acetone and ААд СО" (1.Eq.) is added, after which water is added and the reaction mixture is "stirred overnight at room temperature. The reaction mixture is filtered and washed with acetone. m

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 subsequent purification of the residue by chromatography gives the desired product with a yield of 8595. Alternatively, the dibromide from the reaction with MV5 can be poured into

DMSO (10-2095 mass concentration) and stir for 30 minutes at room temperature. When the reaction is complete, the reaction mixture is poured into water and the resulting precipitate is separated by filtration, the precipitate on the filter is washed with water and dried, obtaining essentially a quantitative yield.

Stage 5: Ammonium acetate (4 equiv.) is added to the aldehyde from the previous stage (Tech.) in CH 5MO" (0.2M) and the resulting mixture is refluxed for 4 hours. Then, the reaction mixture is diluted with EtOAc and washed with a saturated salt solution. The aqueous phase is extracted with E(Ac. The combined organic extracts are washed with brine, dried over sodium sulfate, and concentrated to precipitate a yellow-hot crystalline solid. The mixture is cooled overnight and the nitroolefin is collected by filtration (yield 76905). Evaporation of the liquid phase and purification of the residue by column chromatography (gradient -i elution 10095 toluene -» 1956 E(Ac-toluene) gives an additional amount of nitroolefin (yield 2390). -1 Stage 6: Zinc dust (20 eq.) is suspended in 596 aqueous solution of HCl (8M 2n/595 Naosi" (0.2 eq.) is added to this mixture. The mixture is shaken for 10 min., the aqueous phase is decanted and replaced with fresh 5905 HC, t" again the mixture is shaken for 5 min. and the aqueous phase is separated. Then the amalgam obtained in this way -1 50 zinc-mercury is added to a mixture of nitroolefin (1.0 equiv) and concentrated NH! (8 equiv) in THF (0.04 M nitroolefin/THF). The mixture is gently refluxed for 1 hour. the formation of what) product of art analyzed by TLC. The mixture is cooled to room temperature and the solid is separated by filtration through celite. Concentrated MH OH is added to the liquid phase and the mixture is concentrated on a rotary evaporator. The residue is dissolved in CHCl and concentrated MNAOH. The aqueous phase is extracted with СНоСИ» and the organic phase is washed with saturated salt solution, dried over sodium sulfate and concentrated. Purification by column chromatography gave the desired product (yield 6590).

Stage 7: To methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|vgthoxy)benzoate (Tech.) and eat) saturated Manso" (0, 14M) in SNHS" (0.07M) add o-toluenesulfonyl chloride (1.Eq.). After 1 hour, the mixture is poured into a saturated solution of sodium bicarbonate and extracted with СНоСи». The combined organic phase is washed with 60 saturated salt solution, dried over sodium sulfate and purified by column chromatography (gradient elution using a mixture of 20950 E(OAc-hexane - 25095 EAc-hexane), obtaining the desired product with a yield of 86905.

Step 8: The resulting ester is hydrolyzed by stirring with tn Mahon (5 eq.) in THF (0.07M) and sufficient MeOonH to give a clear solution. The reaction is monitored by TLC (1096 Meon-SNoSiI») after the disappearance of the starting substance. The mixture is heated in an oil bath at 602C for 2 hours. The mixture is concentrated, diluted with HO and acidified to pH 2-4 using 1 M CARRIER. The aqueous phase is extracted with Es and the organic phase is washed with saturated salt solution, dried over sodium sulfate and concentrated to give the desired product in a yield of 9295. High-resolution mass spectrometry calcd. for (C z9NameSIMOOBZyNI 679,2028, found 679,2031.

Example (2: 4-(2-(1-benzhydryl-5-chloro-2--2-isopropylsulfonyl)amino|ethyl)-1H-indol-3-yl)stoxy|benzoic acid

Stage 1: This compound is prepared from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and isopropylsulfonyl chloride by the procedure of example 1, step 7, yield 5590. 70 Step 2: The ester intermediate is hydrolyzed according to step 8 of example 1 to give the title acid, yield 8195. High-resolution MS calcd. for

ISz5Na5SIM2O5Z'ANI 631.2028, found 631.2029.

Example C: 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-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and 1 -butanesulfonyl chloride by the procedure of example 1, stage 7 with a yield of 61905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9095. MS high-resolution calculations. for 20. ISzveNa7SIM2O5Z' NOT 645.2185, found 6452185.

Example 4: 4-2-11-benzhydryl-5-chloro-2-(2-1(1-methyl-1H-imidazol-4-yl)usulfonylamino)ethyl)-1H-indol-3-ilyethoxy)benzoic acid

Step 1: To methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (Step 6, Example 1) (1.0 eq. .) and BM (3.Eq.) or pyridine (0.Eq.) in СНоСИ» (0.05M) add 1-methylimidazole-4-sulfonyl chloride (1.2 eq.). The reaction is monitored by TLC (1095 Meon-SnSiI) and the mixture is heated if necessary. Through ЗОхв. the mixture is poured into a saturated sodium bicarbonate solution and extracted

SNOSI". The combined organic phase was washed with brine, dried over sodium sulfate and purified by column chromatography to give 92905 g of the desired product. с зо Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 8995. MS high-resolution calculations. for -

ISzvNazzSIMAO5 ANI 669,1933, found 669,1932. "IS

Example 5: 4-2-P1-benzhydryl-2-(2-(5-bromo-6-chloro-3-pyridinyl)sulfonyl|Iaminoethyl)-5-chloro-1H-indol-3-yl|ieethoxy)benzoin - the acidity of the

Stage 1: This compound is prepared from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and

C-bromo-2-chloropyridine-5-sulfonyl chloride by the procedure of example 1, stage 7 with a yield of 7496.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9875. MS high-resolution calculations. for shsh with ISa7NzoVgOSi2M5O5Z'ANI 778.0539, found 778.0544.

Example 6: ; » 4-(2-(1-benzpdryl-5-chloro-2-12-IR(1K)-7,7-dimethyl-2-oxobicyclo|2.2.1)hept-1-yl|Imethylisulfonyl)amino|ethyl) -1

N-indol-3-yl)ethoxy|Ibenzoic acid

Stage 1: This compound is prepared from methyl -I 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and (1k)--)-10-camphorsulfonyl chloride by the procedure of example 1, stage 7 with a yield of 77905.

Step 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with step 8 of Example 1, obtaining the acid indicated in the title with a yield of 9495. High resolution MS calcd. for 50. ISaoNazSIMoOvZ'N) 739.2603, found 739.26. - Example 7:

He 4-(2-711-benzhydryl-5-chloro-2-(2-H(methylsulfonyl)methyl|sulfonyl)amino)ethyl/|-1H-indole-3-ilyethoxy)benzoic acid

Stage 1: This compound is prepared from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and ( methanesulfonyl)methanesulfonyl chloride by the procedure of Example 4, step 1, yield 43905. (F) Step 2: The ester intermediate is hydrolyzed according to Example 117, step 2, to give the title acid in yield 9595. High Resolution MS calculation for

ИЗаНззСИМ2О752 NO 681.1491, found 681.1489. in Example 8: 4-(2-711-benzhydryl-5-chloro-2-(2-(12-(1-naphthyl)ethyl|sulfonylamino)ethyl|-1H-indol-3-yl)ethoxy)benzoic acid

Stage 1: This compound is prepared from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and 2 -(1-naphthyl)ethanesulfonyl chloride by the procedure of Example 1, step 7 in a yield of 60905. 65 Step 2: The intermediate, which is an ester, is hydrolyzed in accordance with step 8 of Example 1 to give the title acid in a yield of 10095. MS of high distinguishing calculations for

ISlaNzeSIM2OBZANI 743.2341, found 743.2338.

Example 9: 4-2-11-benzhydryl-5-chloro-2-12-(I(2-nitrobenzyl)sulfonyl)amino|ethyl)-1H-indol-3-yl)ethoxy|Ibenzoic acid

Stage 1: This compound is prepared from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and 2 -nitro-d-toluenesulfonyl chloride by the procedure of example 1, stage 7 with a yield of 82965.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 8595. MS high-resolution calculations. for 70. ISZENZASIMA3O, NO 724,1879, found 724,1877.

Example 10: 4-2-P1-benzhydryl-5-chloro-2-(2-1(3,4-dichlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Iethoxy)benzoic acid

Stage 1: This compound is prepared from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and 75 (3,4-dichlorophenyl)methyl|sulfonyl chloride by the procedure of example 1, stage 7 with a yield of 8295.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 8695. MS high-resolution calculations. for

ISzeNzzSiIzM2O55'NI 747.1249, found 747.1249.

Example 11: 4-(2-(1-benzhydryl-5-chloro-2-(2-C(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-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and

I(3,5-dichlorophenyl)methyl|sulfonyl chloride by the procedure of example 1, stage 7 with a yield of 100905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of Example 1, obtaining the acid indicated in the title with a yield of 9895. High resolution MS calcd. for

ISzeNzzSiIzM2O55'NI 747.1249, found 747.1249. at

Example 12: 4-(2-711-benzhydryl-5-chloro-2-(2-(113-(trifluoromethyl)benzyl|sulfonylamino)ethyl|-1H-indol-3-yl)ethoxy)benzoic acid He

Stage 1: This compound is prepared from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and t (3-(trifluoromethyl)phenyl|methyl|sulfonyl chloride by the procedure of example 1, stage 7 with a yield of 74905. hE

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 8695. MS high-resolution calculations. for t (SloNzaSIRzM2O55'NI 747.1902, found 747.1904. rch-

Example 13: 4-(2-71-benzhydryl-5-chloro-2-(2-(14-(trifluoromethyl)benzylsulfonyl)amino)ethyl/1|-1H-indole-3-ilyethoxy)benzoic acid

Stage 1: This compound is prepared from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and 40. (S-(trifluoromethyl)phenyl|methyl|sulfonyl chloride by the procedure of example 1 stage 7 with a yield of 77905. - c Stage 2: The intermediate compound, which is a complex ether, is hydrolyzed in accordance with stage 8c of example 1, obtaining the indicated in the title acid with a yield of 8395. MS of high resolution calculated for "» ISloNzaSiezZM2OB'ANI 747.190»5, found 747.1901.

Example 14: 4-(2-(/1-benzhydryl-5-chloro-2-(2-(4-fluorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid -I Stage 1: This compound is prepared from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and

C4-fluorophenyl)methyl|sulfonyl chloride by the procedure of example 1, stage 7 with a yield of 8690. ч Stage 2: The intermediate compound, which is an ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9495. MS of high distinction of calculations for

ISZENZASIEM2O55 ANI 697,1934, found 697,1938.

Kz Example 15: 4-2-11-benzhydryl-5-chloro-2-(2-C(4-chlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid

Stage 1: This compound is prepared from methyl bv 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|Iethoxy)benzoate (stage b, example 1) and (4-Chlorophenyl)methyl|sulfonyl chloride by the procedure of Example 1, step 7 with a yield of 73905. o Step 2: The intermediate compound, which is an ester, is hydrolyzed in accordance with step 8 of Example 1, obtaining the title acid with a yield of 9995. MS high resolution computing for

ISZENZASI2M2O55NI 713.1638, found 713.1643. 60 Example 16: 2-(2--(d-aminobenzyl)sulfonyl|amino)ethyl)-4-12-(11-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoic acid

Stage 1: To methyl 4-2-11-benzhydryl-5-chloro-2-12-(2-nitrobenzyl|benzyl)isulfonyl)amino|ethyl)-1H-indol-3-yl)ethoxy|benzoate, example 9, stage 1 (1.Eq.) in CH 25Si" (0.014M) add a mixture of stannous chloride dihydrate (II) (3.Eq.), 65 dissolved in concentrated HCl. After 16 hours, the mixture is alkalized (pH 10) with Zn Mahon and extracted with СНоСі.

The combined organic phase is washed with brine, dried over sodium sulfate, and purified by column chromatography (using an elution gradient of 2095 E(OAc-hexane -» 5095 EAc-hexanes)) to give 83905 of the desired product.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 8395. MS high-resolution calculations. for

ISzenzeSIMzO5 ANI 694.2137, found 694.2136.

Example 17: 4-2-11-benzhydryl-5-chloro-2-(2-Y(dimethylamino)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid

Stage 1: This compound is prepared from methyl 70 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and of dimethylsulfamoyl chloride by the procedure of example 1, stage 7 with a yield of 49905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9595. MS high-resolution calculations. for

ISzaNzaSIMzo5' ANI 632,1981, found 632,1984.

Example 18: 4-22-P1-benzhydryl-5-chloro-2-(2-1(3,4-difluorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Iethoxy)benzoic acid

Step 1: To 3,4-difluorobenzyl bromide (1.0 eq.) in HO (0.74M) is added sodium sulfite (1.Eq.). The mixture is refluxed for 16 hours, then cooled to room temperature. The white precipitate was filtered and dried to give 9595 of sodium sulfonate intermediate.

Stage 2: To sodium 3,4-difluorobenzylsulfonate (7, eq.) in СНоСии» (0.76M) add DMF (5, eq.) and BOSI» (ZOeq.). After 1 hour, the mixture is concentrated and subjected to azeotropic distillation with toluene. The residue is suspended in СНоСИ» (0.38M) and methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indole-3-ilyethoxy)benzoate is added (stage 6, example 1 ) (1.Eq.) and saturated Manso" (0.76M). After 1 hour, the mixture is poured into NaO and extracted

SNOSI". The combined organic phase is washed with a saturated salt solution, dried over sodium sulfate, and the mixture is purified by column chromatography (using a gradient elution of 2095 E(OAc-hexanes -» 4095

EtOAc-hexanes), obtaining 9495 of an intermediate compound, which is a complex methyl ether. and)

Stage C: The complex methyl ether is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9395. High-resolution MS calcd. for |C z9NazSIg2MoOB5Z'AN|I 715.184, found 715.1843. Example 19: 4-2-11-benzhydryl-5-chloro-2-(2-1(2-naphthylmethyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid -

Stage 1: Intermediate sulfonyl chloride is obtained from 2-(bromomethyl)naphthalene by the procedure of example 18, stage "g 1-2 with a yield of 34965.

Stage 2: Complex methyl ether is obtained from sulfonyl chloride and methyl y-4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|Hyethoxy)benzoate (stage b, example 1) by the procedure of example 1, stage 7 with output 58905.

Stage 3: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 7495. MS high-resolution calculations. for

ISzaNa7SIMOOBO t | 729.2185, found 729.2189. "

Example 20: with c 3-(1(2-11-benzhydryl-3-I(2-(4-carboxyphenoxy)ethyl/|-5-chloro-1H-indol-2-ylethyl)amino|sulfonyl)methyl)benzoin acid;" Stage 1: Intermediate sulfonyl chloride is obtained from methyl 3-(bromomethyl)benzoate by the procedure of example 18, stages 1-2.

Stage 2: Complex methyl ether is obtained from sulfonyl chloride and methyl -I 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|Hyethoxy)benzoate (stage b, example 1) by the procedure of example 1, stage 7 with output 23905.

Sh- Stage 3: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the diacid indicated in the title with a yield of 9395. MS of high resolution calculations. for 50. ИСаоНз5СИМ2О7З'Н) 723.1926, found 723.1932. - Example 21:

He 4-(2-711-benzhydryl-5-chloro-2-(2-H(E)-2-phenylethenyl|sulfonyl)amino)ethylI-1H-indol-3-yl)ethoxy) benzoic acid

Stage 1: Trans-y-styrenesulfonyl chloride is added to methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage 6, example 1) by the procedure of Example 1, step 7, giving the product of

EXIT 66905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 and F) of example 1, obtaining the acid indicated in the title with a yield of 9895. MS high-resolution calculations. for ko ISloNz5SIM2OB ANI 691.2028, found 691.2034.

Example 22: in 0 4-2-(1-benzhydryl-5-chloro-2-(2--(trifluoromethyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid

Step 1: Trifluoromethylsulfonyl chloride is added to methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (Step 6, Example 1) by the procedure of Example 1, stage 7, yielding product with a yield of 4995.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 b5 of example 1, obtaining the acid indicated in the title with a yield of 10095. MS high-resolution calculations. for

ISzzNovSIezM2OB5ANI 657.1432, found 657.1435.

Example 23: 4-(2-(1-benzhydryl-5-chloro-2-2-(cyclopropylsulfonyl)amino|)ethyl)-1H-indol-3-yl)ethoxy|benzoic acid

Step 1: Cyclopropanesulfonyl chloride is added to methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (Step 6, Example 1) by the procedure of Example 1, stage 7, yielding product with a yield of 7595.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 8495. MS high-resolution calculations. for

ISz5NazzSIM2OB ANI 629.1872, found 629.1874. 70 Example 24: 4-(2-71-benzhydryl-2-(2-(1H3,5-bis(trifluoromethyl)benzyl|sulfonyl)amino)ethyl|-5-chloro-1H-indol-3-ilyethoxy)benzoin acid

Stage 1: 3,5-bis is added to methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage 6, example 1) (trifluoromethyl/ibenzylsulfonyl by the procedure of Example 1, step 7, affording 7/5 product in 7995 yield.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 8195. MS high-resolution calculations. for

ИСлиНаззСИг6М2О5ZANI 815.1776, found 815.1776.

Example 25: 2-(I(2-11-benzhydryl-3-(2-(4-carboxyphenoxy)ethyl|/|-5-chloro-1H-indol-2-ylethyl)amino|sulfonyl)benzoic acid

Stage 1: Methyl (2-chlorosulfonyl )benzoate by the procedure of Example 1, step 7, to give the product in a yield of 10095.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of Example 1, obtaining the acid indicated in the title with a yield of 6195. High resolution MS calcd. for

ISzeNzzSIM2O7'ANI 709.177, found 709.1772. and)

Example 26: 4-(2-(1-benzhydryl-5-chloro-2-2-(2-naphthylsulfonyl)amino|ethyl)-1H-indol-3-yl)ethoxy|benzoic acid

Stage 1: 2-naphthalene sulfonyl chloride is added to methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage 6, from example 1) by the procedure of Example 1, step 7, giving the product with a yield of 53905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 "g of example 1, obtaining the acid indicated in the title with a yield of 10095. MS high-resolution calculations. for

ISl2Na5SIM2OBANI 715.2058, found 715.2034. -

Example 27: 1-4-2-11-benzhydryl-5-chloro-2-(2-S(3,5-dichlorophenyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid

Stage 1: 3,5-dichlorobenzenesulfonyl chloride is added to methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage 6, example 1) by the procedure of Example 1, step 7, yielding product 60905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 from c of example 1, obtaining the acid indicated in the title with a yield of 8895. MS high-resolution calculations. for

И ISzvNa4СИзМ2О55НИ 733.1092, found 733.1096. and? Example 28: 4-(2-/1-benzhydryl-5-chloro-2-(2-1(3,4-dichlorophenyl)sulfonyl|amino)ethyl)-1H-indol-3-ilyethoxy)benzoin

Acid -I Stage 1: To methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage 6, example 1) add 3, 4-dichlorobenzenesulfonyl chloride by the procedure of example 1, step 7, obtaining the product with a yield of 60905. their Step 2: The intermediate compound, which is an ester, is hydrolyzed in accordance with step 8 5r of example 1, obtaining the acid indicated in the title with a yield of 8075. MS high resolution computing. for sh- ISzvNayayaiSIzM2O55NI 733.1092, found 733.1094.

Example 29: 4-2-P1-benzhydryl-5-chloro-2-(2-X((2,3-dichlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid

Stage 1: Add (2.3 -dichlorophenyl)methyl|sulfonyl chloride by the procedure of Example 1, step 7, to give the product in a yield of 50905.

F) Stage 2: The resulting ester is hydrolyzed by mixing with KOH (67 mg, bq.) in a mixture of THF (ml), MeOnH (5 ml) and NaO (2 ml). The reaction is monitored by TLC (1095 Meon-CH»Si») after the disappearance of the starting substance.

The mixture is stirred overnight at room temperature and then concentrated, diluted with H 50 and acidified to pH 2-4 using 1M CARRIER. The aqueous phase is extracted with EtOAc and the organic phase is washed with saturated salt solution, dried over sodium sulfate and concentrated to give the desired product in a yield of 9895. High resolution MS calcd. for (SzoNzzSiIzM2O55'ANI 747.1249, found 747.1254.

Example 30: 4-2-P1-benzhydryl-5-chloro-2-(2-1(2,4-dichlorobenzyl)sulfonyl|amino)ethyl)-1H-indole-3-yl|ethoxy)benzoic acid 65 Stage 1 : To methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage 6, example 1) add (2,4-dichlorophenyl) methyl|Isulfonyl chloride by the procedure of Example 1, step 7, to give the product in a yield of 9895.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 2 of example 29, obtaining the acid indicated in the title with a yield of 9095. MS high-resolution calculations. for 5. ISzeNzzSizMoOBZ'N) 747.1249, found 747.1255.

Example 31: 4-2-P1-benzhydryl-5-chloro-2-(2-1(2,4-dichlorobenzyl)sulfonyl|amino)ethyl)-1H-indole-3-yl|ethoxy)benzoic acid

Stage 1: To methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage 6, example 1) is added (2-chlorophenyl) methyl|sulfonyl chloride by the procedure of Example 1, step 7, to give product 70 in a yield of 86905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 2 of example 29, obtaining the acid indicated in the title with a yield of 9095. MS high-resolution calculations. for

ISZENZASI2M2O55-NO 713.1638, found 713.1644.

Example 32: 4-2-P1-benzhydryl-5-chloro-2-(2-N(4-chloro-2-nitrobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Ethoxy)benzoic acid

Stage 1: Add (|(4- chloro-2-nitro)umethyl|sulfonyl chloride by the procedure of Example 1, step 7, to give the product in a yield of 74905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 2 of example 29, obtaining the acid indicated in the title with a yield of 9095. MS high-resolution calculations. for

ISzeNzzSi»2M3075 ANI 758.1489, found 758.1494.

The method of their E: o

The acid obtained by method A or by any of the following methods can be used as a substrate for a palladium-catalyzed amination reaction using a base, an amine, a phosphine ligand, and a palladium reagent. -

Example 33: 1-4-(2-(1-benzhydryl-2-2-((benzylsulfoyl)amino|ethyl)-5-morpholin-4-yl-1H-indol-3-yl)ethoxy|benzoic acid

Stage 1: Tris(dibenzylideneacetone) dipalladium (0) (0.01 eq), 2-(di-tert-butylphosphino)diphenyl (0.04 eq), sodium t-butoxide (2.4 eq) and acid are charged to the flask from stage 8 (1, Equiv.). 1.5 ml of toluene (1.0 M) is added to the flask, followed by the addition of morpholine (1.2 equiv.). The reaction mixture is boiled "

Refrigerate for five hours. The reaction mixture is distributed between 595% hydrogen chloride with acid and diethyl ether. The organic layer is washed with distilled water, then with a saturated solution. salt, dried over sodium sulfate and concentrated. The product is purified by preparative LC-MS, yielding 7.890 µl? desired product. MS of high resolution calculations. for |S.43NazMzOv65'ANI 730.2945, found 730.2945.

Example 34: 4-2-P1-benzhydryl-5-chloro-2-(2-S((2-cyanobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid -I Stage 1 : (2-Cyanophenyl)umethanesulfonyl chloride is obtained according to example 18, stage 1-2 (yield of crude substance 10096).

Step 2: The title compound is prepared from 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl)benzoic acid methyl ester (stage b, example 1) and 500 (2-cyanophenyl)methanesulfonyl chloride by the procedure of example 1, stage 7 in the form of a solid white substance with a yield of 7295.

Ge Stage 3: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 7495. MS (ERI) t/2 (M-1) 702.0; MS of high resolution calculations. for C 0 Na 5 SIMaO 55 (M-1): 704, 1980. Found: 704,1984. E. anal. calculation for

B SaoNzaSIMzOBe: C, 68.22; N, 4.87; M, 5.97. Found: C, 67.92; H, 5.11; M, 5.54.

Example 35:

F) 4-22-P1-benzhydryl-5-chloro-2-(2-1(3,5-difluorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Iethoxy)benzoic acid ka Stage 1: Intermediate sulfonyl chloride is obtained from 3,5-difluorobenzyl bromide by the procedure of example 18, stage 1-2 with a yield of 9595. in Stage 2: Complex methyl ether is obtained from sulfonyl chloride and methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl) -5-chloro-1H-indole-3-yl|hiethoxy)benzoate (stage b, example 1) by the procedure of example 1, stage 7 with a yield of 78905.

Stage 3: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the diacid indicated in the title with a yield of 8395. MS high-resolution calculations. for 65 ISzenzzSIroMoOB'N) 715.184, found 715.1842.

Example 36:

4-2-P1-benzhydryl-5-chloro-2-(2-1(3-cyanobenzyl)sulfonyl|amino)ethyl)-1H-indole-3-yl|ethoxy)benzoic acid

Stage 1: (3-cyanophenyl)umethanesulfonyl chloride is prepared according to example 18, stages 1-2 (yield of crude substance 10096).

Stage 2: The title compound is prepared from 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|Hyethoxy)benzoic acid methyl ester (stage b, example 1) and (33-cyanophenyl)methanesulfonyl chloride according to example 1, stage 7.

Stage 3: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 8195. MS (ERI) t/2 (M-1) 702.1; MC of high 7/0 resolution calculations. for So loNzzSIMzOBZ (M-1): 702,1834. Found: 702,1833. E. anal. calculation for

S.oNzaSIMzO55.0.8NhO: C, 67.00; H, 5.00; M, 5.86. Found: C, 67.22; H, 5.19; M, 5.44.

Example 37: 4-2-P1-benzhydryl-5-isochloro-2-(2-((4-cyanobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Iethoxy)benzoic acid

Stage 1: (4-cyanophenyl)umethanesulfonyl chloride is obtained according to example 18, stages 1-2 (yield 75 N of crude substance 100965).

Stage 2: The title compound is prepared from 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|Hyethoxy)benzoic acid methyl ester (stage b, example 1) and (4-cyanophenyl) methanesulfonyl chloride according to example 1, stage 7.

Stage 3: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 7775. MS (ERI) t/2 (M-1) 702.1; MS of high resolution calculations. for C 30Na5SIMzO55 (Ma1): 704, 1980. Found: 704,1981. E. anal. calculation for

SaoNzaSIMzOBe: S, 68.22; N, 4.87; M, 5.97. Found: C, 68.09; H, 4.97; M, 5.73.

Example C8: 4-(2-711-benzhydryl-5-chloro-2-(2-(44-(1-piperidinylsulfonyl)benzyl|sulfonyl)amino)ethyl/|-1H-indole-3-ilyethoxy)c benzoic acid

Stage 1: (4-(piperidine-1-sulfonyl)phenyl|methanesulfonyl chloride is obtained according to example 18, about stages 1-2 (yield of crude substance 10096).

Stage 2: The title compound is prepared from 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|Hyethoxy)benzoic acid methyl ester (stage b, example 1) and Ha 4-(piperidine-1-sulfonyl)phenyl|methanesulfonyl according to example 1, stage 7.

Stage 3: The intermediate compound, which is an ester, is hydrolyzed in accordance with stage 8 - example 1, obtaining the acid indicated in the title with a yield of 7395. MS (ERI) t/2 (M-1) 824.2; MS of high resolution calculation. for Со 44НазСИМа3О75" (M-1): 824.2236. Found: 824.2246. E. anal. calculation for

S.ANAaSIM50755.0.5H20: C, 63.25; H, 5.43; M, 5.03. Found: C, 62.85; H, 5.64; M, 4.64. in

Example 39: h- 4-(2-2-(2-44-(aminosulfonyl)benzyl|sulfonyl)amino)ethyl)-1-benzhydryl-5-chloro-1H-indole-3-ilyethoxy)benzoic acid

Stage 1: (4-sulfamoylphenyl)methanesulfonyl chloride is prepared according to example 18, stage 1-2 (yield "crude 10096).

Stage 2: The title compound is obtained from the methyl ester of 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl)benzoic acid (stage b) , example 1) and c (4-sulfamoylphenyl)methanesulfonyl chloride according to example 1, step 7. "» Step 3: The intermediate compound, which is an ester, is hydrolyzed according to step 8 of example 1, obtaining the title acid with a yield 6995. MS (ERI) t/2 (M-1) 755.9; high-resolution MS calculated for C z9Nz5SIM53O752 (M-1): 756.1613. Found: 756.1612. Electronic anal. calculated for - I SzeNzeSIM5075": C, 61.77; H, 4.79; M, 5.54. Found: C, 61.93; H, 5.12; M, 5.19.

Example 40: 4-(2-71-benzhydryl-5-chloro-2-(2-(4-methanesulfonylphenyl-methanesulfonylamino)ethyl/|-1H-indole-3-ilyethoxy)benzoic acid

Stage 1: (4-methanesulfonylphenyl)methanesulfonyl chloride is prepared according to example 18, stages 1-2 and (yield of crude substance 100905).

III Stage 2: The title compound is obtained from 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|Hyethoxy)benzoic acid methyl ester (stage b, example 1) and (4-methanesulfonylphenyl)methanesulfonyl chloride according to example 1, stage 7.

Stage 3: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 7595. MS (ERI) t/2 (M-1) 755.0; MS of high resolution calculations. for C 40NzaSIM2O,5Z" (Mya1): 757.1804. Found: 757,1804. E. anal. calculation for ime) С.оНзвСИМ2О,5».НоО: С, 61,96; N, 5.07; M, 3.61. Found: C, 61.82; H, 5.10; M, 3.48.

Example 41: 6o /4-(2-11-benzhydryl-5-chloro-2-(2-(4-diethylsulfamoylphenyl-methanesulfonylamino)ethyl|-1H-indol-3-yl)ethoxy)benzoic acid

Stage 1: (4-Diethylsulfamoylphenyl)methanesulfonyl chloride is obtained according to example 18, stages 1-2 (yield of crude substance 100905).

Stage 2: The title compound is prepared from 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indole-3-yl-ethoxy)benzoic acid methyl ester 65 (stage b, example 1 ) and (4-diethylsulfamoylphenyl)methanesulfonyl chloride according to example 1, stage 7.

Stage 3: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 6695. MS (ERI) t/2 (M-1) 812.1; MS of high resolution calculations. for C 43Na5SIMa3O.5" (M1): 814.2382. Found: 814.2385. E. anal. calculation for 50 SaZNaaSIM3O752.0.3 H2O: C, 62.99; H, 5.48; M, 5.14. Found: C, 62.91; H, 5.67; M, 4.79.

Example 42: 4-(3-/1-benzhydryl-5-chloro-2-(2-phenylmethanesulfonyl-aminoethyl)-1H-indol-3-yl|Ipropyl)ubenzoic acid

Stage 1: A mixture of methyl-4-iodobenzoate (5.3g, 20.2mmol), allyl alcohol (1.78g, 30.3mmol), Manso uz (4.24g, 50.5mmol), RY(OAc) (0 ,14g, 0.bOmmol), (n-Vy)AMVg (6.55g, 20.2mmol) and molecular sieves 4-A (41g) in 7/0 anhydrous DMF (bOml) were stirred at room temperature for 4 days. The reaction mixture is filtered through celite, the filtrate is poured into water and extracted with EIUAs. The organic layer was washed with a saturated salt solution, dried (Ma»5O)) and concentrated in vacuo. Flash chromatography (silica gel, 10-2095 E(Ac-hexane)) afforded 2.11 g (8595 based on reduced starting material) of the desired 4-(3-oxopropyl)benzoic acid methyl ester as a clear oily substance.

Stage 2: To a solution of 5-chloro-2-methylindole (0.86g, 5.2mmol) and 4-(3-oxopropyl)benzoic acid methyl ether (1.0g, 5.2mmol) in methylene chloride (5Oml) is added TFO ( 1.78g, 15.mmol), followed by triethylsilane (1.81g, 15.mmol). The reaction mixture is stirred overnight, quenched with saturated Manso solution (5 Oml) and the organic layer is washed with saturated ManHsSoO solution, water, saturated salt solution and dried (Ma»SO)). The solvent is removed under reduced pressure and the residue is purified by flash column chromatography using a mixture of 10-20906 E(OAc/hexanes) to give the desired product in a yield of 9495 (1.67g).

Step 3: To a solution of the product from step 2 (1.66g, 4.8bmmol) in DMF (20ml) is added Mann (6095 in mineral oil, 0.24g, 5.83mmol) under a Mo atmosphere. The mixture was stirred for 1 hour at room temperature, followed by the dropwise addition of benzhydryl bromide (1.8 g, 7.29 mmol) in DMF (Bml). The reaction mixture was stirred at room temperature overnight. Water (500 ml) is added to the reaction mixture, extracted with EtOAc, washed with a saturated salt solution, dried (Ma»3O);) and concentrated under reduced pressure to a brown syrup, which is purified by chromatography on silica gel using a mixture of 1095 E(OAc/hexanes as o eluent, obtaining 4 as a white solid with a yield of 5995 (1.47 g).

Stage 4: The product obtained in the previous stage (1.46g, 2.87mmol) is dissolved in HCl (14.5ml), followed by the addition of MB5 (1.02g, 5.7mmol) and benzoyl peroxide (2mg). The reaction mixture is boiled under reflux for 1 hour (until the starting material disappears). This mixture is cooled to room temperature, filtered, and the solid is washed with HCl/. The filtrate is evaporated to a brown residue, which is dissolved in a mixture of acetone (40 ml) and water (4 ml), then Na90CO3 (1.75 g, 3, 16 mmol) is added to this solution, and after stirring at room temperature overnight, it is filtered through Celite , the solvent is evaporated under reduced pressure and water is added to the residue. The mixture is extracted with E(UAc, washed with saturated -

335 with a salt solution, dried (Ma»5O);) and evaporated to a syrup, which is purified with a mixture of 1095 EdAs/hexanes to give 2-formylindole (1.13 g) with a yield of 7595. Alternatively, the dibromide from the reaction with MV5 can be poured into

DMSO (10-2095 mass concentration) and stir for 30 minutes at room temperature. After completion of the reaction, the mixture is poured into water and the precipitate formed as a result is separated by filtration, the precipitate on the filter is washed with water and dried, obtaining essentially a quantitative yield. "

Stage 5: To the solution of 2-formylindole from the previous stage (0.52g, Tmmol) in SNUMO" (6.2ml) add MNAOAc shsh s (0.077g, Tmmol), the mixture is refluxed for 1 hour, then add MH /OAc (0.077tg, 1mmol), refluxing is continued for an additional 1 hour, then MNAOAc (0.077g, Tmmol) is added again, refluxing is continued for 1 hour. The reaction mixture is allowed to cool to room temperature, E(Ac (50 ml) is added, followed by the addition of 100 ml

water The aqueous layer is extracted with EtOAc and the combined organic layers are washed with saturated salt solution, dried ((Ma»3SO)) and evaporated to a yellow foam, which is subjected to chromatographic purification using a mixture of 1090

EtOAc/hexanes as eluent to give 6 as a yellow foam in 68905 (0.38g).

Che Stage 6: 7p(No) is obtained by adding NasIi o (3.4g, 7.2mmol) to a mixture of dust 2p (34.68g, 530.35mmol) and "iz" 596 NSI (Zvml) in a 100Oml flask, and this mixture vigorously stir for 1 hour. The aqueous phase is decanted, Zvml 595 NSI is added again and the mixture is stirred for 1 hour. The aqueous phase is decanted. Come on

The solid was added to vinyl nitro compound 6 (15g, 26.57mmol) in THF (bbOml) and concentrated NOSI with (64.5ml). This mixture is stirred at room temperature for 1 hour, then refluxed for 15 minutes. The reaction mixture is cooled to room temperature and filtered through Celite. An aqueous solution of MH.OH (200 ml) is added to the filtrate and stirred for 15 min. and THF are removed at

Reduced pressure. The aqueous layer is extracted with CHNOCl, the combined organic layers are washed with saturated salt solution, dried (Ma»3O),) and concentrated to a brown foam, which is purified by column chromatography, eluting (F, column first with CHNOCl to remove nonpolar impurities, then with a mixture of 295 Meon/Snei with to isolate the desired amine with a yield of 46965 (6.1 g).

Stage 7: Add o-toluenesulfonyl chloride 6o (, eq.) to the amine (Eq.) and saturated MnSO" (0.14 M) in SNHC" (0.07 M). After 1 hour, the mixture is poured into a saturated sodium bicarbonate solution and SNeoSi is extracted."

The combined organic phase was washed with brine, dried over sodium sulfate and purified by column chromatography to give 8495 g of the desired product.

Stage 8: The resulting ester is hydrolyzed by mixing with tn Maon (bq.) in THF (0.07M) and a sufficient amount of Meon to obtain a clear solution. The reaction is monitored by TLC (10956 Meon-CH Si") 65 by the disappearance of the starting substance. The mixture is stirred overnight at room temperature and then concentrated, diluted with H.O. and acidified to pH 2-4 using 1M HCl. The aqueous phase is extracted

EtOAc and the organic phase are washed with a saturated salt solution, dried over sodium sulfate and concentrated, obtaining the desired product with a yield of 10095. High-resolution MS calcd. for |C 40Naz7SIM»O,Z'ANI 677.2235, found 677.224.

Example 43: 4-(3-P1-benzhydryl-5-chloro-2-(2-1(3,5-dichlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Ipropyl)benzoic acid

Step 1: This compound was prepared from the intermediate synthesized in Example 42, Step 6, and (3,5-dichlorophenyl)methyl|sulfonyl chloride by the procedure of Example 42, Step 7, to give the desired product in a yield of 9895. 70 Step 2: Intermediate, which is an ester, is hydrolyzed in accordance with stage 8 of example 42, obtaining the acid indicated in the title with a yield of 10095. MS high-resolution calculations. for

ISloNz5SIzM20.5'ANI 745.1456, found 745.1458.

Example 44: 4-(3-P1-benzhydryl-5-chloro-2-(2-1(3,4-dichlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Ipropyl)benzoic acid

Step 1: This compound was prepared from the intermediate synthesized in Example 42, Step 6, and (3,4-dichlorophenyl)methyl|sulfonyl chloride by the procedure of Example 43, Step 7 to give the desired product in a yield of 96905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 42, obtaining the acid indicated in the title with a yield of 9895. MS high-resolution calculations. for 20. ISaoNzvSizM2O,Z'NI 745.1456, found 745.1458.

Example 45: 4-(2-(1-benzhydryl-5-chloro-2-(2-(methylsulfonyl)amino|ethyl)-1H-indol-3-yl|ethoxy)benzoic acid

Stage 1: Methanesulfonyl chloride is added to methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage 6, example 1) by the procedure of example 4, stage 1, obtaining a product with a yield of Z.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 i) of example 1, obtaining the acid indicated in the title with a yield of 10095. MS high-resolution calculations. for

ISzzNaiSIM2O5 ANI 603.1715, found 603.1717.

Example 46: 4-(2-(1-benzhydryl-5-chloro-2-2-(phenylsulfonyl)amino|ethyl)-1H-indol-3-ilyethoxy)benzoic acid

Stage 1: Benzenesulfonyl chloride is added to methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage 6, - example 1) by the procedure of example 4 , stage 1, obtaining a product with a yield of 9090 g.

Stage 2: The intermediate compound, which is an ester, is hydrolyzed according to stage 8-

From example 1, obtaining the acid indicated in the title with a yield of 9095. MS high-resolution calculations. for M

ИЗвНаззСИМ2О5 АНИ 665.1872, found 665.1869.

Example 47: 4-(2-7-1-benzhydryl-5-chloro-2-(2-(13-"trifluoromethyl)benzyl|sulfonyl)amino)ethyl/|-1H-indole-3-ilyethoxy)benzoic acid"

Stage 1: Add 4III-( trifluoromethyl)phenyl|methyl)usulfonyl chloride by the procedure of example 1, stage 7, . obtaining a product with a yield of 7490. and? Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 8695. MS high-resolution calculations. for 45. ISdonZaSIRzM2O5'NN) 747.1902, found 747.1904. -I Example 48: 2-(I(2-((2-11-benzhydryl-3-(2-(4-carboxyphenoxy)ethyl|/|-5-chloro-1H-indol-2-ylethyl)amino|sulfonylethyl) )aminoic

Carbonyl)benzoic acid their Stage 1: To methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage 6, 5th example 1) add 2-phthalimidoethanesulfonyl chloride by the procedure of example 1, stage 7, obtaining a product with a yield of 7895.

Ge Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9995. MS high-resolution calculations. for

ISl2NzvSIMzOv ANI 780.2141, found 780.2148.

Example 49: 4-2-C1-benzhydryl-5-chloro-2-(2-((3-(pyridinylmethyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid

F) Stage 1: Add (S -pyridylmethyl)sulfonyl chloride by the procedure of Example 1, step 7, giving the product in yield 5295. in Step 2: The intermediate compound, which is an ester, is hydrolyzed according to step 8 of example 1, obtaining the title acid in yield 9495. MS of high distinction of calculations for

ISzvNzaSIMzO55-NI 678.18349, found 678.18277.

Example 50: 4-2-C1-benzhydryl-5-chloro-2-(2-(I(4-(pyridinylmethyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid 65 Stage 1 : To methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage 6, example 1) is added (4-pyridylmethyl)sulfonyl chloride by the procedure of Example 1, step 7, giving product with a yield of 57905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 10090. t/2 (M-1) MS high resolution calculations. for (SzaNaSIMaO5Z-NI 678.18349, found 678.18249.

Example 51: 4-2-C1-benzhydryl-5-chloro-2-(2-(I(2-(pyridinylmethyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid

Stage 1: To methyl 4-O2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage 6, example 1) is added (2-pyridylmethyl) sulfonyl chloride by the procedure of Example 1, step 7, to give product 4295 in 70 yield.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 5695. MS high-resolution calculations. for

ISzvNzaSIMzO55-NI 678.18349, found 678.18312.

Example 52: 75 4-13-11-benzhydryl-5-chloro-2-(2-C(2,6-dimethylbenzyl)sulfonyl|iamiso)ethyl)-1H-indol-3-yl|Ipropyl)/benzoic acid

Stage 1: The sulfonyl chloride intermediate is prepared from 2,6-dimethylbenzyl chloride by the procedure of Example 18, Stages 1-2 in a yield of 10095.

Step 2: The methyl ester is prepared from the sulfonyl chloride and the intermediate of Example 42, Step 8 by the procedure of Example 42, Step 7 in a yield of 30905.

Stage 3: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 42, obtaining the acid indicated in the title with a yield of 10095. MS high-resolution calculations. for

ISlgNalyaSIM2Ou-NO 703.24028, found 703.23973.

Example 53: Ha 4-(2-(/1-benzhydryl-5-chloro-2-(2-Y(cyclohexylmethyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid

Stage 1: Intermediate sulfonyl chloride is obtained from (bromomethyl)cyclohexane by the procedure of example 18, i9) of stage 1-2 with a yield of 10095.

Stage 2: The complex methyl ether is obtained from sulfonyl chloride and methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|Hyethoxy)benzoate (stage b, example 1 ) by the Ge procedure of example 1, stage 7 with output 20905.

Stage 3: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 - example 1, obtaining the acid indicated in the title with a yield of 7395. MS high-resolution calculations. for "I

ISzeNaiSIM2O55-NO 683.23519, found 683.23474.

Example 54: - 4-2-/1-benzhydryl-5-chloro-2-(2-1(4-nitrobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl)ethoxy)benzoic acid -

Step 1: The sulfonyl chloride intermediate is prepared from 4-nitrobenzyl bromide by the procedure of Example 18, steps 1-2 in a yield of 9595.

Stage 2: Complex methyl ether is obtained from sulfonyl chloride and methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|Hyethoxy)benzoate (stage b, example 1) by the procedure of example 1, stage 7 with a yield of 80905. - c Stage 3: The intermediate compound, which is a complex ether, is hydrolyzed in accordance with stage 8c of example 1, obtaining the compound indicated in the title with a yield of 9095. MS high-resolution calculations. for "» ISZENZASIMAO7'ANI 724,1879, found 724,1884.

Example 55: 4-12-(1-benzhydryl-5-chloro-2-(2-1(3-nitrobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid -I Stage 1 : Intermediate sulfonyl chloride is obtained from 3-nitrobenzyl bromide by the procedure of example 18, stage 1-2 with a yield of 9595. 7 Stage 2: Complex methyl ether is obtained from sulfonyl chloride and methyl "g" 4-(2-(2-(2-aminoethyl)-1 -benzhydryl-5-chloro-1H-indol-3-yl|Hyethoxy)benzoate (stage b, example 1) by the procedure of example 1 stage 7 with a yield of 8595. 7 Stage 3: The intermediate compound, which is an ester, is hydrolyzed in accordance with to stage 8

From Example 1, obtaining the title compound with a yield of 8595. High resolution MS calcd. for

ISZENZASIM307'ANI 724.1879, found 724.1885.

Example 56: 4-22-P1-benzhydryl-5-chloro-2-12-((2-nitrobenzyl)sulfonyl)amino|ethyl)-1H-indol-3-yl)propyl)benzoic acid

Stage 1: To methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6,

F, example 42) add 2-nitro-α-toluenesulfonyl chloride by the procedure of example 1, step 7, obtaining the product with a yield of 6595.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 10095. High-resolution MS calcd. for

ISlonzeSIMzOv8'ANI 722.2086, found 722.2088.

Example 57: 4-(3-P1-benzhydryl-5-chloro-2-(2-1(4-fluorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Ipropyl)benzoic acid

Stage 1: To methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6, example 42) is added )methanesulfonyl chloride by the procedure of Example 1, step 7, to give the product in a yield of 77905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 6895. MS high-resolution calculations. for

ISlonzeSieM20.5'ANI 695.2141, found 695.2145.

Example 58: 4-(3-1-benzhydryl-5-chloro-2-(2-(44-(trifluoromethyl)benzylsulfonyl)amino)ethyl/1|-1H-indol-3-yl)ipropyl)benzoic acid

Stage 1: To methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage 6, example 42) is added (4-trifluoromethylphenyl) methanesulfonyl chloride by the procedure of example 1, step 7, to give the product with a yield of 5090. 70 Step 2: The intermediate compound, which is an ester, is hydrolyzed according to step 8 of example 1, obtaining the title acid with a yield of 10095. High resolution MS calcd. for

ISliNazoSIgz3M20, ANI 745.2109, found 745.2114.

Example 59: 4-(3-71-benzhydryl-5-chloro-2-(2-(13-trifluoromethyl)benzyl|sulfonylamino)ethyl|-1H-indol-3-yl)ipropyl)benzoic acid

Stage 1: To methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6, example 42) is added (3-trifluoromethylphenyl )methanesulfonyl chloride by the procedure of Example 1, step 7, to give the product in a yield of 5690.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 82906. MS high-resolution calculations. for

ISliNzoSIEM20.5 ANI 745.2109, found 745.211.

Example 60: 4-(3-P1-benzhydryl-5-chloro-2-(2-PSH(4-chlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Ipropyl)benzoic acid

Stage 1: Add (4- chlorophenyl)methanesulfonyl chloride by the procedure of example 1, stage 1, obtaining the product with a yield of 74905. o

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 7995. MS high-resolution calculations. for

ISloNzeSi2M20.5' ANI 711.1846, found 711.1847. Example 61: 4-(3-P1-benzhydryl-5-chloro-2-(2-S(2-pyridinylmethyl)sulfonyl|aminoethyl)-1H-indol-3-yl|Ipropyl)benzoic acid -

Stage 1: Add pyridine-2 -ylmethanesulfonyl chloride by the procedure of Example 4, step 1, obtaining the product with a yield of 7595. -

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9695. High-resolution MS calcd. for

ISZENZESIMAZO,ZANI 678.2188, found 678.2187.

Example 62: 4-(3-P1-benzhydryl-5-chloro-2-(2-(3-pyridinylmethyl)sulfonyl|aminoethyl)-1H-indol-3-yl|Ipropyl)benzoic acid "

Stage 1: Pyridine-3 is added to methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6, from example 42) -ylmethanesulfonyl chloride by the procedure of example 4, stage 1, obtaining the product with a yield of 7595. ;" Step 2: The ester intermediate is hydrolyzed according to step 8 of Example 1 to give the title acid in a yield of 88905.

Example 63: -I 4-(3-P1-benzhydryl-5-chloro-2-(2-I(4-pyridinylmethyl)sulfonyl|aminoethyl)-1H-indol-3-yl|Ipropyl)benzoic acid

Stage 1: To methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6,

Ш- example 42) add pyridin-4-ylmethanesulfonyl chloride by the procedure of example 4, stage 1, obtaining a product with a yield of 7595.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 7795. MS high-resolution calculations. for

From ISZENZESIMAO,5-NI 676.20423, found 676.20405.

Example 64: 4-(3-P1-benzhydryl-5-chloro-2-(2-CH(2-chlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Ipropyl)benzoic acid

Stage 1: Intermediate sulfonyl chloride is obtained from 3-chlorobenzyl bromide by the procedure of example 18, stages 1-2.

F) Stage 2: Complex methyl ether is obtained from sulfonyl chloride and methyl ka 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)ubenzoate (stage b) , example 42) by the procedure of example 1, stage 7 with a yield of 10905. in Stage 3: The intermediate compound, which is an ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the title compound with a yield of 10095. High-resolution MS calcd. for

ISloNzeSi2M20.5-NO 709.17000, found 709.16961.

Example 65: 4-(3-P1-benzhydryl-5-chloro-2-(2-I(3-nitrobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|propyl)benzoic acid 65 Stage 1: Intermediate sulfonyl chloride is obtained from 3-nitrobenzyl bromide by the procedure of example 18, stages 1-2.

Stage 2: The complex methyl ether is obtained from sulfonyl chloride and methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)ubenzoate (stage b, example 42 ) by the procedure of example 1, stage 7 with output 43905.

Stage 3: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the title compound with a yield of 8895. High-resolution MS calcd. for

ISloNzeSIM2O,-NO 720.19405, found 720.19398.

Example 66: 4-(3-P1-benzhydryl-5-chloro-2-(2-(3-chlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Ipropyl)benzoic acid 70 Stage 1: Intermediate sulfonyl chloride is obtained from 3-chlorobenzyl bromide by the procedure of example 18, stages 1-2.

Stage 2: The complex methyl ether is obtained from sulfonyl chloride and methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)ubenzoate (stage b, example 42 ) by the procedure of example 1, stage 7 with output 27905.

Stage 3: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the title compound with a yield of 9395. High-resolution MS calcd. for

ISloNzeSi2M20.5-NO 709.17000, found 709.16963.

Example 67: 4-(3-P1-benzhydryl-5-chloro-2-(2-S((2,5-dichlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Ipropyl)benzoic acid

Stage 1: The intermediate sulfonyl chloride is prepared from 2,5-dichlorobenzyl bromide by the procedure of example 18, stages 1-2.

Stage 2: The complex methyl ether is obtained from sulfonyl chloride and methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)ubenzoate (stage b, example 42 ) by the procedure of example 1, stage 7 with output 59905. p

Stage 3: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the title compound with a yield of 10095. High resolution MS calcd. for i)

ИСлоНз5СИзМ20.45-НИ 743.13103, found 743.13079.

Example 68: 4-(3-P1-benzhydryl-5-chloro-2-(2-I(3-methoxybenzyl)sulfonyl)amino)ethyl)-1H-indol-3-yl|Ipropyl)/benzoic acid c zo Stage 1: Intermediate sulfonyl chloride is obtained from 3-methoxybenzyl bromide by the procedure of example 18, stage Kk 1-2.

Stage 2: Complex methyl ether is obtained from sulfonyl chloride and methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)ubenzoate (stage b, example 42) by the procedure of example 1, stage 7 with output 20905. -

Stage 3: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the title compound with a yield of 10095. High resolution MS calcd. for

ISliNzeSIM2O5Z-NO 705.21954, found 705.21909.

Example 69: 4-(3-I2-(2-(2-aminobenzyl)sulfonyl|amino)ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoic acid "

Stage 1: The intermediate compound from stage 1 of example 56 is treated with ZpSiI by the procedure described in stage 1 of example 16, obtaining a complex amine ether with a yield of 99965. Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8a of example 1, obtaining the acid indicated in the title with a yield of 10095. MS high-resolution calculations. for

ISloNzvSIM3045-NO 690.21988, found 690.21941.

Example 70: -I 4-(3-P1-benzhydryl-5-chloro-2-(2-S(2-methylbenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Ipropyl)ubenzoic acid

Stage 1: Intermediate sulfonyl chloride is obtained from 2-methylbenzyl bromide by the procedure of example 18, stages - 1-2 with a quantitative yield. their Step 2: The complex methyl ether is prepared from the sulfonyl chloride and the intermediate obtained in Example 42, Step 6, by the procedure of Example 42, Step 7 in a yield of 50905.

Sh- Stage 3: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 from example 42, obtaining the acid indicated in the title with a yield of 9395. MS high-resolution calculations. for

ISliNzeSIM2O)-NO 689.22463, found 689.22421.

Example 71: 4-2-11-benzhydryl-5-chloro-2-(2-1(4-trifluoromethoxybenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid

F) Stage 1: Intermediate sulfonyl chloride is obtained from 4-trifluoromethoxybenzyl bromide by the procedure of example 18, stages 1-2 with quantitative yield.

Stage 2: The complex methyl ether is obtained from sulfonyl chloride and methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|Hyethoxy)benzoate (stage b, example 1) by the procedure of example 1, stage 7 with output 48905.

Stage 3: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 8595. MS high-resolution calculations. for

ISLONZASIEMOO65-NO 761.17054, found 761.17031. 65 Example 72: 4-22-P1-benzhydryl-5-chloro-2-(2-C1(2-fluoro-6-nitrobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid

Stage 1: The sulfonyl chloride intermediate is prepared from 2-fluoro-6b-nitrobenzyl bromide by the procedure of Example 18, Stages 1-2 in quantitative yield.

Stage 2: The complex methyl ether is obtained from sulfonyl chloride and methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|Hyethoxy)benzoate (stage b, example 1 ) by the procedure of example 1, stage 7 with output 91905.

Stage 3: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 100905. t/2 (M-1) 740.05. 70 Example 73: 4-2-11-benzhydryl-5-chloro-2-(2-S(2-dichlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid

Stage 1: Intermediate sulfonyl chloride is obtained from 3,5-dichlorobenzyl bromide by the procedure of example 18, stages 1-2 with theoretical yield.

Stage 2: The complex methyl ether is obtained from sulfonyl chloride and methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|Hyethoxy)benzoate (stage b, example 1 ) by the procedure of example 1, stage 7 with output 100905.

Stage 3: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 81905. t/2 (M-1) 747.2. MS of high resolution calculations. for (SzoNazzSizMoOvZ - NO 745.11030, found 745.10954.

Example 74: 4-22-P1-benzhydryl-5-chloro-2-(2-H1(2,6-difluorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid

Stage 1: The sulfonyl chloride intermediate is prepared from 2,6-difluorobenzyl bromide by the procedure of Example 18, Stages 1-2 in a yield of 9595.

Stage 2: Complex methyl ether is obtained from sulfonyl chloride and methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|Hyethoxy)benzoate (stage b, example 1) by the procedure of example 1, stage 7 with output 86905. o

Stage 3: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 71905. t/2 (M-1) 714. MS high-resolution calculations. for (CzoHzZSIR2M2O5-NI 713.16940, found 713.16906. s zo Example 75: 4-(2-71-benzhydryl-5-chloro-2-(2-((b-chloro-3-pyridinyl)methyl|sulfonyliamino )ethyl|-1H-indol-3-yl)ethoxy)benzoin - a acid "E

Step 1: (6b-Chloro-3-pyridinyl)methanol (1.0 eq.) is placed in dichloromethane and stirred overnight with carbon tetrabromide (1.5 eq.) and 1,3-bisidiphenylphosphino)propane (0.75 eq.). Ether is added to the solution, and filtration followed by concentration of the filtrate gives (b-chloro-3-bromomethyl)pyridine with a yield of 62905. M

Step 2: The sulfonyl chloride intermediate is prepared from the product of step 1 by the procedure of example 18, steps 1-2.

Stage C: The complex methyl ether is obtained from sulfonyl chloride and methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|Hyethoxy)benzoate (stage b, example 1 ) by the procedure of example 1, stage 7 with output 78905.

Stage 4: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 from c of example 1, obtaining the acid indicated in the title with a yield of 8995. MS high-resolution calculations. for

Y ISzvNazSi»Mz3O55-NI 712.14452, found 712.14420. and? Example 76: 4-(2-71-benzhydryl-5-chloro-2-(2-4(5,6-dichloro-2-(Ipyridinyl)methyl|sulfonylamino)ethyl|-1H-indol-3-yl)ethoxy )nizoic acid -I Step 1: 5,6-dichloro-3-pyridinemethanol (1.0 eq.) is placed in dichloromethane and stirred overnight with carbon tetrabromide (1.5 eq.) and 1,3-bisidiphenylphosphino)propane (0 .75 square meters). Ether is added to the solution, and

Ш-filtration followed by concentration of the filtrate gives 5,6-dichloro-3-bromomethylpyridine in a yield of 13096. Their Step 2: The sulfonyl chloride intermediate is obtained from the product of step 1 by the procedure of Example 18, steps 1-2 with 5p Yield 81905.

Ш- Stage C: Complex methyl ether is obtained from sulfonyl chloride and methyl

He 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|Hyethoxy)benzoate (stage b, example 1) by the procedure of example 1, stage 7 with a yield of 79905 .

Stage 4: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 10975. High-resolution MS calcd. for

ISzvNazaSizMz3O55-NO 746.10554, found 746.10549.

F) Example 7: 4-2-P1-benzhydryl-5-chloro-2-(2-(3-methoxybenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl ethoxy)benzoic acid

Stage 1: Intermediate sulfonyl chloride is obtained from 3-methoxybenzyl bromide by the procedure of example 18, stages 1-2 with a yield of 6895.

Stage 2: The complex methyl ether is obtained from sulfonyl chloride and methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|Hyethoxy)benzoate (stage b, example 1 ) by the procedure of example 1, stage 7 with output 68905.

Stage 3: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 b5 of example 1, obtaining the diacid indicated in the title with a yield of 9395. MS high-resolution calculations. for

ISZENZZSIZMO OB AMA) 731,1953, found 731,1947.

Example 78: 4-2-11-benzhydryl-5-chloro-2-(2-C(3,5-dimethylbenzyl)sulfonyl|amino)ethyl)-1H-indole-3-ilyethoxy)benzoic acid

Step 1: The sulfonyl chloride intermediate is prepared from 3,5-dimethylbenzyl bromide by the procedure of Example 18, steps 1-2 in a yield of 3895.

Stage 2: The complex methyl ether is obtained from sulfonyl chloride and methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|Hyethoxy)benzoate (stage b, example 1 ) by the procedure of example 1, step 7 with a yield of 38905. 70 Step 3: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with step 8 of example 71, obtaining the diacid indicated in the title with a yield of 8890. pt/2 (M-1) 705.0. High-resolution MS calculated for |C4HzoSIM2O55-NO 705.21954, found 705.21916.

Example 79: 4-2-P1-benzhydryl-5-chloro-2-(2-N(2-methylbenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid

Step 1: The sulfonyl chloride intermediate is prepared from 2-methylbenzyl bromide by the procedure of Example 18, steps 1-2 in a yield of 3595.

Stage 2: The complex methyl ether is obtained from sulfonyl chloride and methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|Hyethoxy)benzoate (stage b, example 1 ) by the procedure of example 1, stage 7 with output 35905.

Stage 3: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 71, obtaining the diacid specified in the title with a yield of 9090. pt/» (M-1) 691.0. MS of high resolution calculations. for (C40NaUSIMoO55-NO 691.20389, found 691.20350.

Example 80: 4-2-P1-benzhydryl-5-chloro-2-(2-1(2,6-dichlorobenzyl)sulfonyl|amino)ethyl)-1H-indole-3-yl|ethoxy)benzoic acid

Stage 1: Intermediate sulfonyl chloride is obtained from 2,6-dichlorobenzyl bromide by the procedure of example 18, stages 1-2 with a yield of 395. o

Stage 2: The complex methyl ether is obtained from sulfonyl chloride and methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|Hyethoxy)benzoate (stage b, example 1 ) by the procedure of example 1, stage 7 with a yield of 3905. c zo Stage 3: The intermediate compound, which is an ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the diacid indicated in the title with a yield of 92905. t/2 (M-1 ) 745.0 -

Method C "g

From I u. en EVSE Y I Ve - yy sho shnyavy "MK shk "vk Y z a s: MY v shk sho ee She y y r Ne rn inn i se ge ish "V » - Zhe y o, - A shchi ih y Z She - ;" гч ж 5 а.

The intermediate amine, synthesized using method A, is treated with chloromethylsulfonyl chloride under Schott and Baumann conditions, or under anhydrous conditions with an organic base, obtaining an intermediate compound that is chloromethylsulfonamide. This intermediate can be treated with various nucleophiles in DMF in the presence of suitable organic bases, M,M-diisopropylethylamine, triethylamine, etc., and heated to complete

F) completion of the reaction. The resulting intermediates are then hydrolyzed to give the final compound. ka In the following examples, the synthesis is carried out by method C: examples 81-86 and 118-121.

Example 81: 4-(2-H-benzhydryl-5-chloro-(2-H(phenylsulfanyl)methylsulfonyl)amino)ethyl/|-1H-indole-3-ylethoxy)benzoic acid

The title compound is synthesized as shown in method C.

Step 1: Chloromethanesulfonyl chloride is added to methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (Step 6, Example 1) by the procedure of Example 1, stage 1, yielding product 65 YIELD 99905.

Step 2: To methyl 4-2-P1-benzhydryl-5-chloro-2-(2-H(chloromethyl)sulfonylamino)ethyl)-1H-indole-3-yl|ethoxy)benzoate (0.080M, 1.00eq .) and iso-RhoMEI (334 eq.) in M,M-dimethylformamide add thiophenol (2.1-2.eq.) and the mixture is stirred at 1202C for 3.5 days. The reaction mixture is diluted

EUDAs and washed with water and saturated salt solution. The combined organic phase is dried over magnesium sulfate and purified by flash chromatography.

Stage 3: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9390. t/72 (M-1) 709.11. MS of high resolution calculations. for |(SzoNaz5SIMoOv5»o-NI 709.16031, found 709.15999,

Example 82: 70... 4-(2-71-benzhydryl-5-chloro-2-(2-(2,6-dimethylphenylsulfanyl-methanesulfonylamino)ethyl|-1H-indol-3-yl)ethoxy)benzoic acid

Stage 1: To methyl 4-2-11-benzhydryl-5-chloro-2-(2-((chloromethyl)sulfonylaminoethyl)-1H-indol-3-yl|ethoxy)benzoate, example 81, stage 1, add 2, 6-dimethylthiophenol by the procedure of example 81, stage 2. The product is purified by 75 flash chromatography using a mixture of 25956 E(UAc/hexane with a yield of 32905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 42, obtaining the acid indicated in the title with a yield of 8095. pt/2 (M-1) 751.0. MS of high resolution calculations. for |С4НзоСИМоО55о-НИ 737.19161, found 737.19128.

Example 83: 4-(2-11-benzhydryl-5-chloro-2-(2-(2-methoxyphenylsulfanyl-methanesulfonylamino)ethyl|-1H-indol-3-yl)ethoxy)benzoic acid

Stage 1: To methyl 4-2-11-benzhydryl-5-chloro-2-(2-((chloromethyl)sulfonylaminoethyl)-1H-indol-3-yl|ethoxy)benzoate, example 81, stage 1, add 2- methoxythiophenol by the procedure of example 81, stage 2. The product is purified by flash chromatography using a mixture of 3090 E(UAs)/hexane with a yield of 3690.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 42, obtaining the acid indicated in the title with a yield of 9490. t/2 (M-1) 753.3. MS of high resolution calculations. for (СаоНаУСИМов52-НИ 739.17088, found 739.17052.

Example 84: Gas 4-(2-41-benzhydryl-5-chloro-2-(2-(2-chloro-6-methylphenylsulfanylmethanesulfonylamino)ethyl|-1H-indol-3-yl)ethoxy)benzoic acid in

Stage 1: To methyl "I 4-2-11-benzhydryl-5-chloro-2-(2-((chloromethyl)sulfonylaminoethyl)-1H-indol-3-yl|ethoxy)benzoate, example 81, stage 1, add 2-chloro-b6-methylthiophenol by the procedure of example 81, stage 2. The product is purified by flash chromatography using a mixture of 25956 EUAs/hexane with a yield of 4690.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 42, obtaining the acid indicated in the title with a yield of 100905. pt/» (M-1) 771.2. MS of high resolution calculations. for |(СаоНазвСи»МоО55о-НИ 757.13699, found 757.13730.

Example 85: « 40. 4-(2-71-benzhydryl-5-chloro-2-(2-(3,5-dichlorophenylsulfanyl-methanesulfonylamino)ethyl|-1H-indol-3-yl)ethoxy)benz shsh c oyla acid and Stage 1: To methyl "" 4-2-11-benzhydryl-5-chloro-2-(2-((chloromethyl)sulfonylaminoethyl)-1H-indol-3-yl|ethoxy)benzoate, example 81, stage 1 , add 3,5-dichlorothiophenol by the procedure of Example 81, step 2. The product is purified by flash chromatography using a mixture of 25956 EtOAc/hexane in a yield of 4090. -and Step 2: The intermediate compound, which is an ester, is hydrolyzed according to step 8 of example 42, obtaining the acid specified in the title with a yield of 9895. t/2 (M-1) 793.2. MS of high and distinction calculations. for |SzoNazzSiIzMoOv5o-NI 777.08237, found 777.08159. Example 86: 500 4-(2-41-benzhydryl-5--chloro-2-(2-(3,4-dimethoxyphenylsulfanylmethanesulfonylamino)ethyl|-1H-indol-3-yl)ethoxy)b and enoic acid from Stage 1: To methyl 4-2-P1-benzhydryl-5-chloro-2-(2-H(chloromethyl)sulfonylamino)ethyl)-1H-indol-3-yl|1ethoxy)benzoate, Example 81, Stage 1 , add 3,4-dimethoxythiophenol by the procedure of Example 81, stage 2. The product is purified by flash chromatography using a mixture of 3596 EtOAc/hexane with

EXIT 4095.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 and F) of example 42, obtaining the acid indicated in the title with a yield of 9995. t/2 (M-1) 783.3. MS of high-resolution computing. for |C44NzoSIM»2O755-NI 769.18144, found 769.18120.

Method Ю 60 b5 шт є вк шу ШШШ и чин ша дивы и узы дныни 70 Я aa I still shk

E Sha;

The intermediate amine, synthesized using method A, is treated with chloroethanesulfonyl chloride in anhydrous conditions in the presence of an organic base, obtaining an intermediate compound that is a vinyl sulfonamide. This intermediate compound can be treated with various nucleophiles in DMF in the presence of a suitable organic base, Nipidz base, triethylamine, etc. Heat it until the reaction is complete.

The resulting intermediates are then hydrolyzed to yield the final compound. and)

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

Example 87: 4-(2-11-benzhydryl-5-chloro-2-(2-(2-morpholin-4-ylethanesulfonylamino)ethyl/|-1H-indole-3-ylethoxy)isobenzoic acid

The title compound is synthesized as shown in method 0. -

Stage 1: To methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (0.16M, «g 1.0 equiv.) , stage 6, example 1, and triethylamine (2.3 eq.) in THF was added dropwise 2-chloroethanesulfonyl chloride (1.2 eq.). After 4 hours, the mixture was poured into a saturated salt solution and extracted with EtOAc. The combined organic phase dried over magnesium sulfate and purified by column chromatography to give vinyl sulfonamide in a yield of 7595.

Step 2: Morpholine is added to the product from step 1 in 1-propanol. After 5 hours, the reaction mixture is evaporated to dryness and then redissolved in EtOAc. The organic phase is washed with a saturated salt solution, dried over magnesium sulfate and purified by column chromatography, obtaining the desired complex methyl ether with "

OUTPUT 89905. shsh s Stage 3: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8. of example 1, obtaining the acid specified in the title with a yield of 8995. t/72 (M-1) 702.17. MS of high and resolution calculations. for |SzaNaoSIMAzOv65-NI 700.2535, found 700.22500.

Example 88: 4-(2-71-benzhydryl-5-chloro-2-(2-(2-pyrazol-1-ylethanesulfonylamino)ethyl|-1H-indol-3-ilyethoxy)benzoic acid - and Stage 1: This compound obtained in 9095 yield from intermediate of example 87, step 1 and 1H-pyrazole by the procedure of example 87, step 2, except that the mixture is heated at 802C for 18 hours.

Step 2: The intermediate compound, which is an ester, is hydrolyzed in accordance with step 8" of example 1, obtaining the acid indicated in the title with a yield of 61905. t/72 (M-1) 681.24. MS of high 5p resolution calculations. for |С37НазСИМАО55-Н| 681.19439, found 681.19407.

Example 89: 4-(2-71-benzhydryl-5-chloro-2-(2-(2-phenylaminoethanesulfonylamino)ethyl|-1H-indol-3-yl)ethoxy)

HYA6) benzoic acid

Step 1: This compound was prepared in 5095 yield from the intermediate of Example 87, Step 1 and aniline by the procedure of Example 87, Step 2, except that the mixture was heated at 802C for 8 days.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 98905. t/72 (M-1) 706.26. MC of high and) calculation resolution. for |С0НзвСИМзО55-НИ 706.21479, found 706.21452. Example 90: 4-(2-71-benzhydryl-5-chloro-2-(2-(12-(1,4-dioxa-8-azaspiro|4.5|dec-8-yl)ethyl|Isulfonylamino)ethyl| -1H-indole-3-boyl)ethoxy)benzoic acid

Step 1: This compound was prepared in 8295 yield from the intermediate of Example 87, Step 1 and 1,4-dioxa-8-azaspiro(4.5|decane) by the procedure of Example 87, Step 2, except that the mixture was stirred overnight.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 b5 of example 1, obtaining the acid indicated in the title with a yield of 10090. t/2 (M-1) 756.2. MS of high resolution calculations. for |C/4H44SiIzO75-NI 756.25157, found 756.25142. -BO0-

Example 91: 4-(2-(1-benzhydryl-5-chloro-2-12-((2-14-(2-pyridinyl)-1-piperazinylethyl)isulfonyl)amino|ethyl)-1H-indole-3- il)et oxy|benzoic acid

Step 1: This compound was prepared in 86905 yield from the intermediate of Example 87, Step 1 and 1-pyridin-2-yl-piperazine by the procedure of Example 87, Step 2, except that the mixture was stirred overnight.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 10095. pt/2 (M-1) 776.2. MC of high 7/0 resolution calculations. for |C4zNa«SIM5O5-H) 776.26789, found 776.26750.

Example 92: 4-(2-71-benzhydryl-5-chloro-2-(2-(12-(1H-1,2,4-triazol-1-yl)ethyl|Iisulfonylamino)ethyl|-1H-indole- 3-yl)ethoxy)benzoic acid

Step 1: This compound was prepared in 6495 yield from intermediate of Example 87, Step 1 and 75.THN-P1,2,4)triazole by the procedure of Example 87, Step 2, except that the mixture was refluxed for 4 days

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 10095. pt/2 (M-1) 682.1. MS of high resolution calculations. for (Sz6NaSIM5O55-NI 682.18964, found 682.18964.

Example 93: 4-(2-711-benzhydryl-5-chloro-2-(2-(12-(3,5-dimethyl-1H-pyrazol-1-yl)ethylsulfonylamino)ethyl|-1H-indole-3- il)ethoc sy)benzoic acid

Step 1: This compound is obtained in yield 9595 from intermediate of example 87, step 1 and

With,5-dimethyl-1H-pyrazole by the procedure of example 87, stage 2, except that the mixture is refluxed for 24 hours.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 i) of example 1, obtaining the acid indicated in the title with a yield of 6290. t/2 (M-II) 709.2. MS of high resolution calculations. for (SzoNzoSIMAOv5Z-NI 709.22569, found 709.22532.

Example 94: c zo 4-2-1-benzhydryl-5-chloro-2-(2-(112-(3-methyl-1H-pyrazol-1-yl)ethyl|Hisulfonyl)amino)ethyl|-1H-indole -3-yl)ethoxy)benzoic acid -

Step 1: This compound is obtained in a yield of 8895 from intermediate of example 87, step 1 and "

C-methyl-1H-pyrazole by the procedure of example 87, step 2, except that the mixture is stirred overnight.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8-c5 of example 1, except that the pH is adjusted to 4-5, obtaining the acid indicated in the title with a yield of 8690 ppm. t/:2 (M-Y) 695.2. MS of high resolution calculations. for |SzaNa» SIM.O55-NO 695.21004, found 695.20951.

Example 95: 4-(2-711-benzhydryl-5-chloro-2-(2-(12-(4-methyl-1H-pyrazol-1-yl)ethyl|sulfonyl)amino)ethyl/1-1H-indole -Z-iliethoxy)benzoic acid «

Step 1: The present compound was prepared in 8195 yield from intermediate of Example 87, Step 1 and 4-methyl-1H-pyrazole s by the procedure of Example 87, Step 2, except that the mixture was refluxed for 2 days. ;" Step 2: The ester intermediate is hydrolyzed in accordance with step 8 of example 1, except that the pH is adjusted to 4-5 to give the title acid in a yield of 9390. t/2 (M-Y) 695.2. MS of high resolution calculations. for |SzaNa» SIM.O55-NI 695.21004, found 695.20954. -I Example 96: 4-(2-(1-benzhydryl-5-chloro-2-12-(C2-(2K,65)-2,6-dimethyl-1-piperidinylethylusulfonyl)amino|ethyl)-1H-indole - From

s-l)ethoxy|benzoic acid from Stage 1: This compound is obtained in 5495 yield from the intermediate compound of Example 87, Stage 1 and 5r 2,6-dimethylpiperidine by the procedure of Example 87, Stage 2, except that the mixture is heated at 70 C

During the night. from Step 2: The intermediate, which is an ester, is hydrolyzed in accordance with step 8 of example 1, except that the pH is adjusted to 4-5, obtaining the title acid in a yield of 7990. t/2 (M-I ) 726.3. MS of high resolution calculations. for |C44NavSIMzO55-NI 726.27739, found 726.27720.

Example 97: 4-(2-71-benzhydryl-5-chloro-2-(2-(12-(2-thioxo-1-imidazolidinyl)ethyl|sulfonyl)amino)ethyl/|-1H-indole-3-ilyethoxy )benzoic acid and F) Step 1: This compound is prepared in 1795 yield from the intermediate of Example 87, Step 1 and co-imidazolidin-2-thione by the procedure of Example 87, Step 2, except that the mixture is refluxed for C days in Stage 2: The intermediate compound, which is an ester, is hydrolyzed in accordance with stage 8 of example 1, except that the pH is adjusted to 4-5, obtaining the title acid in a yield of 8890. t/2 (M-1 ) 715.3. MS of high resolution calculations. for (C57Na»SIMAO5Z-NI 715.18211, found 715.18161.

Example 98: 4-(2-711-benzhydryl-5-chloro-2-(2-(12-(1,3-thiazolidin-3-yl)ethyl|sulfonylamino)ethyl|-1H-indol-3-yl) ethoxy)benzoic acid

Step 1: This compound was prepared in 3395 yield from the intermediate of Example 87, Step 1 and the thiazolidine by the procedure of Example 87, Step 2, except that the mixture was refluxed overnight.

Step 2: The ester intermediate is hydrolyzed in accordance with step 8 of example 1, except that the pH is adjusted to 4-5 to give the title acid in a yield of 9390.t/2 (M-1) 702.3. MS of high resolution calculations. for |(С37НзвСИМ3О552-НИ 702.18686, found 702.18659.

Example 99: 4-(2-711-benzhydryl-5-chloro-2-(2-(2-(1,2,3|Hygriazol-1-ylethanesulfonylamino)ethyl|-1H-indol-3-yl)ethoxy) benzoic acid 76 Step 1: This compound is prepared in 2395 yield from the intermediate of Example 87, Step 1 and 1nH-P1,2,3)triazole by the procedure of Example 87, Step 2, except that the mixture is refluxed for 5 days.

Step 2: The ester intermediate is hydrolyzed in accordance with step 8 of example 1, except that the pH is adjusted to 4-5 to give the title acid in a yield of 10095. t/2 (M-1) 682.0. MS of high resolution calculations. for (Сз6НазыСИМ5О5З-НИ 682.18964, found 682.18933.

Example 100: 4-(3-71-benzhydryl-5-chloro-2-(2-(2-morpholin-4-ylethanesulfonylamino)ethyl|-1H-indole-3-ylpropyl)benzoic acid

Stage 1: To methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|Ipropyl)benzoate Stage 6, Example 42 (0.16M, 1.0eq .) and triethylamine (2.Eq.) in THF add 2-chloroethanesulfonyl chloride (1.2 Eq.) dropwise. After 4 hours, the mixture is poured into a saturated salt solution and extracted with E(Ac. The combined organic phase is dried over magnesium sulfate and purified by column chromatography, obtaining vinyl sulfonamide.

Step 2: Morpholine is added to the product from step 1 in 1-propanol. After 5 hours, the reaction mixture is evaporated to dryness and then re-dissolved in E(OAc). The organic phase is washed with a saturated salt solution, dried over magnesium sulfate and purified by column chromatography, obtaining the desired complex methyl ether with a yield of 10090.

Stage 3: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 i) of example 1, obtaining the acid indicated in the title with a yield of 85905. t/72 (M-1) 698.12. MS of high resolution calculations. for (SzoNa2SIMzO55-NI 698.24609, found 698.24581.

Example 101: c zo 4-I3-(1-benzhydryl-5-chloro-2-12-(2-(2,6-dimethylpiperidin-1-yl)ethanesulfonylamino|ethyl)-1H-indol-3-yl)propyl benzoic acid -

Step 1: This compound was prepared in 5995 yield from the intermediate of Example 100, Step 1 and 2,6-dimethylpiperidine by the procedure of Example 100, Step 2, except that the mixture was refluxed at 802C for 1 day 17 hours . in.

Stage 2: The intermediate compound, which is an ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 8690. t/72 (M-1) 724.20. MS of high resolution calculations. for |С42НавСИМа3О)5-НИ 724.29813, found 724.29776.

Example 102: 4-I3-(1-benzhydryl-5-chloro-2-12-(2-(3,5-dimethylpyrazol-1-yl)ethanesulfonylamino|ethyl)-1H-indol-3-yl)propyl|benzo ssic acid Step 1: This compound is prepared in quantitative yield from the intermediate of Example 100, Step 1 and 3,5-dimethyl-1H-pyrazole by the procedure of Example 100, Step 2, except that the mixture is boiled with reverse and? refrigerator at 802C for 1 day.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 8995. t/2 (M-1) 707.16. MC of high -I resolution of calculations. for (SlaoNASIMAO)5-NO 707.24642, found 707.24597.

Example 103 and 104: 4-(2-7-11-benzhydryl-5-chloro-2-(2-(2-tetrazol-2-ylethanesulfonylamino)ethyl|-1H-indol-3-yl)oethoxy)benzoic acid, part 4 -(2-11-benzhydryl-5-chloro-2-(2-(2-tetrazol-1-ylethanesulfonylamino)ethyl|-1H-indol-3-yl)oethoxy)benzoic acid

Stage 1: Mixture of methyl ether and 4-2-11-benzhydryl-5-chloro-2-(2-ethenesulfonaminoethyl)-1H-indol-3-yl|ethoxy)benzoic acid (0.2M, 1.Eq.),

A mixture of 1H-tetrazole (4 Equiv.) and iso-Rg2MEI (4.Eq.) in 1-propanol is refluxed overnight.

The mixture is evaporated to dryness and then redissolved in EtOAc. The organic phase is washed with water and saturated salt solution, dried over magnesium sulfate, purified by column chromatography, obtaining two isomers with yields of 41595 and 5290, respectively.

Step 2: The ester intermediates are hydrolyzed according to step 8 i) of Example 1, except that the pH is adjusted to 4-5 to give the title acid, co 4-(2-11-benzhydryl -5-chloro-2-(2-(2-tetrazol-2-ylethanesulfonylamino)ethyl|-1H-indol-3-yl)ethoxy)benzoic acid with a yield of 92906. t/: (M-1) 683.3; into 4-(2-11-benzhydryl-5-chloro-2-(2-(2-tetrazol-1-ylethanesulfonylamino)ethyl|-1H-indol-3-ilyethoxy)benzoic acid with a yield of 83905. t/2 (M -1) 683.3. MS of high resolution calculated for |C z5NzzSiMeO55-NI 683.18489, found 683.18458; 4-(2-71-benzhydryl-5-chloro-2-(2-(2-tetrazole- 1-ylethanesulfonylamino)ethyl-1H-indol-3-yl)ethoxy)benzoic acid with a yield of 8395. MS of high resolution calculated for (C35NazCMeO55-H) 683.18489, found 683.18435. 65 Method E and p. g and - sh. in RI. pe: SHY "In what - EI st I -i what so VSH y i: r. y-y tyy h s ay veEsiya shk yk sho new vysya yah Eh rev nestia vek vu, ny, y y y y y SYA: because NO

PO s sm bat antenna pla la | What: tv pc u

The substituted aromatic nitro compound is treated with ethyl oxalate in the presence of potassium or sodium in an alcoholic solvent. The resulting oxalate ester is treated with a suitable reducing agent, such as "" iron powder, and the resulting amine is subjected to cyclization to indole under reaction conditions. The carboxylate " is then reduced with any reducing agent, lithium-aluminum-hydride, OIVAG. (diisobutylaluminum hydride), etc. and the resulting alcohol is oxidized using reagents such as manganese dioxide, Swern MMO/TRAP conditions, etc. This 2-formylindole is then alkylated by treatment with a strong base such as majnmoO5, -Mann, etc. and then alkylated with a suitable halide. The aldehyde is then treated with nitromethane and a base such as ammonium acetate to give a vinyl nitro intermediate that can be reduced by various agents such as lithium aluminum hydride or 7p(Na) amalgam in NH. The resulting amine is sulfonylated using sulfonyl chloride under biphasic conditions of Schott and Baumann, or under non-aqueous conditions in the presence of -I 20 organic base. This intermediate can be alkylated with reduction at the C3 position with an aldehyde or acetal with a Brønsted or Lewis acid such as trifluoroacetic acid and a reducing agent such as triethylsilane. The intermediate compound obtained as a result is hydrolyzed with a base, Maon, con, GiOH and a mixture of solvents, which includes alcohol, water and tetrahydrofuran. In the following examples 105-107, the synthesis is carried out according to method E. 59 Example 105: 4-2-/1-benzhydryl-b-chloro-2-(2-phenylmethanesulfonyl-aminoethyl)-1H-indole-3-yl|ethoxy) gasoline

F! acid

Stage 1: Ethanol (40 ml, in 100 ml of ether), where diethyl oxalate (27.85 g, in bOml of ether) and 4-chloro-2-nitrotoluene (in 40 ml of ether) are added to potassium (6.24 g) in ether at room temperature. The reaction mixture is stirred at room temperature for 15 hours, followed by sonication for 7 hours, and then pouring 60 into cold INH. After neutralization, the aqueous layer is extracted with EtOAc and the combined organic layers are washed with saturated salt solution and dried. After evaporation, the crude ethyl ether of 3-(4-chloro-2-nitrophenyl)-2-oxopropionic acid is directly used in the next stage without further purification.

Stage 2: To the crude ethyl ether of 3-(4-chloro-2-nitrophenyl)-2-oxopropionic acid (151 mmol) in a mixture of ethanol: glacial NOAc (1:1, v/v, 5 bOml) at room temperature is added iron powder (74.4 g) and the reaction mixture are stirred at reflux for 4 hours. The mixture is filtered and evaporated, obtaining a precipitate, which is redistributed in a mixture of dichloromethane/in NSI. The organic layer is washed with

NS, Manso" and saturated salt solution and dried. Evaporation followed by crystallization (DCM) gave b-chloro-1H-indole-2-carboxylic acid ethyl ether as a light yellow solid (16.8g, 5095 over two steps).

Stage C: To the ethyl ether of 6b-chloro-1H-indole-2-carboxylic acid (8.57g) in THF at 09С, a solution of lithium aluminum hydride (1M, in THF) is added dropwise and the reaction mixture is stirred for 3.5 hours The mixture is quenched with H2O, 1595 Mahon and HO, after which it is filtered and washed with THF. Evaporation of the solvent gives 7.77 g of crude (b-chloro-1H-indol-2-yl)methanol, which is directly used in the next stage. 70 Step 4: Manganese oxide (MI) was added to (b-chloro-1H-indol-2-yl)methanol (37.7 mmol) in THF at 02 and the mixture was stirred at room temperature for 16 hours. The mixture is filtered through celite, washed with THF and

EudAs and evaporate almost to dryness. The solid substance is filtered and washed with a cold mixture of E(Ac/hexane), obtaining 6b-chloro-1H-indole-2-carbaldehyde (6290, in 2 stages).

Stage 5: To b-chloro-1H-indole-2-carbaldehyde (Eq.) in DMF at 02C, Mann (1.25 eq.) is added in portions, 75 followed by benzhydryl bromide (1.4 eq.) and Vi AMI (0 .05 eq.). The mixture is stirred at room temperature for 42 hours, after which it is quenched with cold 0.4N NSI at 0 es. After neutralization, the aqueous layer is extracted with ether, the organic layer is washed with cold NO and dried. Flash chromatography on silica gel gave 1-benzhydryl-b6-chloro-1H-indole-2-carbaldehyde in 4095 yield.

Stage 6: A solution of 1-benzhydryl-b-chloro-1H-indole-2-carbaldehyde (0.5M, Teq.) and MH 2OAc (Teq.) in nitromethane is heated at 952C for 7 hours. The mixture is diluted with E(UAs), washed with water and dried. Evaporation of the volatile components, followed by trituration in an ether/hexane mixture, gives 1-benzhydryl-b-chloro-2-(2-nitrovinyl)-1H-indole with a yield of 48965.

Stage 7: 1-benzhydryl-b-chloro-2-(2-nitrovinyl)-1H-indole (0.1M, Teq) is added dropwise to lithium aluminum hydride (1M in THF, 4eq) in THF at 0 9С .) and the reaction mixture is stirred for 2 hours. with

The mixture is quenched with HO, 1595 Mahon, and HO, filtered through Celite and washed with EtOAc. After evaporation, the residue (He) is purified by column chromatography, obtaining 2-(1-benzhydryl-b-chloro-1H-indol-2-yl)ethylamine with a yield of 40905.

Step 8: To /2-(1-benzhydryl-b6-chloro-1H-indol-2-yl)ethylamine is added phenylmethanesulfonyl chloride by the procedure of example 1, step 7, obtaining c

M-(2-(1-benzhydryl-6-chloro-1H-indol-2-yl)ethyl|-C-phenylmethanesulfonamide with a yield of 9095. i-

Stage 9: Methyl ether 4-(2 -oxoethoxy)benzoic acid (3, Eq.), triethylsilane " (Eq.) and TFO (Eq.). The reaction mixture is stirred at room temperature for 2 days and 20 hours, followed by water treatment. Purification by chromatography on silica gel , followed by reversed-phase HPLC, gives

Zo methyl ether of 4-(2-(/1-benzhydryl-b-chloro-2-(2-phenylmethanesulfonylaminoethyl)-1H-indol-3-yl)ethoxy) benzoic acid with a yield of 35905.

Step 10: The ester intermediate from step 9 is hydrolyzed according to step 8 of Example 1 to give the title acid in yield 6490.

Example 106: 49 d-(2-411-benzhydryl-b-chloro-2-(2-(3,4-dichlorophenylmethane-sulfonylamino)ethyl-1H-indol-3-ilyethoxy)benzoic acid "from Stage 1: 0 To /2-(1-benzhydryl-b-chloro-1H-indol-2-yl)ethylamine, Example 105, Step 7, "(3,4-dichlorophenyl)methanesulfonyl chloride is added by the procedure of Example 105, Step 7, to give

IM-(2-(1-benzhydryl-b6-chloro-1H-indol-2-yl)ethyl|-C-(3,4-dichlorophenyl)methanesulfonamide in quantitative yield.

Stage 2: M-(2-(1-benzhydryl-b-chloro-1H-indol-2-yl)ethyl|-C-(3,4-dichlorophenyl)methanesulfonamide is alkylated with

Ш- reduction, as described in example 105, stage 9, obtaining methyl ether - and 4-(2-71-benzhydryl-b-chloro-2-(2-(3,4-dichlorophenylmethanesulfonylamino)ethyl|-1H-indole- of 3-ylethoxy)benzoic acid with a yield of 38905. o Stage 3: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stages 8 and 20 of example 1, obtaining the acid specified in the title with a yield of 9695. t/2 (M- 1) 747.27.

Example 107: g» 4-(2-711-benzhydryl-b-chloro-2-(2-(3,5-dichlorophenylmethane-sulfonylamino)ethyl/|-1H-indole-3-ylethoxy)benzoic acid

Step 1: 0 To /2-(1-benzhydryl-b-chloro-1H-indol-2-yl)ethylamine, Example 105, Step 7, is added (3,5-dichlorophenyl)methanesulfonyl chloride by the procedure of Example 105, Step 7, to give

HF) IM-(2-(1-benzhydryl-6-chloro-1H-indol-2-yl)ethyl|-C-(3,5-dichlorophenyl)methanesulfonamide in quantitative yield.

Step 2: M-(2-(1-benzhydryl-b-chloro-1H-indol-2-yl)ethyl|-C-(3,4-dichlorophenyl)methanesulfonamide is alkylated with de reduction as described in Example 105, step 9, obtaining 4-(2-71-benzhydryl-b-chloro-2-(2-(3,5-dichlorophenylmethanesulfonylamino)ethyl|-1H-indol-3-ylethoxy)benzoic acid methyl ester 60 with a yield of 3195.

Stage 3: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9595. MS high-resolution calculations. for

ISzenzzSizMoO55 Ma) 769.1068, found 769.1079.

Example 108: bo 4-(2-(/1-benzhydryl-5-chloro-2-(2-((2-cyanobenzyl)sulfonyl|aminoethyl)-1H-indol-3-yl|ethoxy)benzoic acid -B4-

Step 1: The sulfonyl chloride intermediate is prepared from 2-bromomethylbenzonitrile by the procedure of Example 18, steps 1-2 in a yield of 10095.

Stage 2: The complex methyl ether is obtained from sulfonyl chloride and methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|Hyethoxy)benzoate (stage b, example 1 ) by the procedure of example 1, stage 7.

Step 3: The ester intermediate is hydrolyzed according to step 8 of Example 1 to give the title acid in a total yield of 7295. High resolution MS calcd. for С4оНз5СИМаОв (М'-1): 704.1980, found 704.1984. 70 Example 109: 4-2-11-benzhydryl-5-chloro-2-(2-I(tetrahydro-2H-pyran-2-ylmethyl)sulfonylamino)ethyl)-1H-indol-3-yl|ethoxy)benzoin acid

Stage 1: The sulfonyl chloride intermediate is prepared from 2-bromomethyltetrahydropyran by the procedure of Example 18, Stages 1-2 in a yield of 10095.

Stage 2: The complex methyl ether is obtained from sulfonyl chloride and methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|Hyethoxy)benzoate (stage b, example 1 ) by the procedure of example 1, stage 7.

Stage 3: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the title acid in a total yield of 2095. High resolution MS calcd. for SzvNzvSIMoOv5 (M-1): 685.2145, found 685.2143.

Example 110: 4-2-11-benzhydryl-2-(2-(1,3-benzoxazol-2-ylmethyl)sulfonyl|amino)ethyl)-5-chloro-1H-indol-3-yl|ieethoxy)benzoin a acid

Stage 1: The sulfonyl chloride intermediate is prepared from 2-bromomethylbenzoxazole by the procedure of Example 18, step 1-2 with a yield of 10095.

Stage 2: Complex methyl ether is obtained from sulfonyl chloride and methyl i) 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|Hyethoxy)benzoate (stage b, example 1) by the procedure of example 1, stage 7.

Stage 3: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8c of Example 1, obtaining the title acid in a total yield of 2695. High-resolution MS calcd. for SloNz5SIMzOv (MT): 720.1930, found 720.1924. -

Example 111: "g 4-2-P1-benzhydryl-5-chloro-2-(2-I(cyanomethyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid

Stage 1: Intermediate sulfonyl chloride is obtained from 3-bromomethyl-I(1,2,oxadiazole by the procedure of example 18, stage 1-2 with a yield of 10095. M

Stage 2: The complex methyl ether is obtained from sulfonyl chloride and methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|Hyethoxy)benzoate (stage b, example 1 ) by the procedure of example 1, stage 7.

Stage 3: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of Example 1, obtaining the title acid in a total yield of 5995. High resolution MS Calc. pt") c for Sz4NyaziSIMaOv (M'-1): 628.1668, found 628.1662. . Example 112: and? 4-2-P1-benzhydryl-5-chloro-2-(2-11(3Z-thienylmethyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid

Stage 1: Intermediate sulfonyl chloride is obtained from 3-bromomethyl 3-bromomethylthiophene by the procedure of example 18, stages 1-2 with a yield of 10095. -I Stage 2: Complex methyl ether is obtained from sulfonyl chloride and methyl 4-(2-(2-(2-aminoethyl) )-1-benzhydryl-5-chloro-1H-indole-3-yl|Hyethoxy)benzoate (stage b, example 1) by the procedure of example 1, stage 7. Stage 3: The intermediate compound, which is an ester, is hydrolyzed in accordance with step 8 5r of example 1, obtaining the acid indicated in the title with a total yield of 2595. MS high-resolution calc. w- for C32Naz1SIM»OBZ» (M-1): 683.1447, found 683.1445.

Ge Example 113: 4-(2-(1-benzhydryl-5-chloro-2-(2-(2-methylpyrrolidin-1-yl)ethanesulfonylamino|ethyl)-1H-indol-3-yl)ethoxy|benzoic acid

Step 1: This compound was prepared from the intermediate of Example 87, Step 1 and 2-methylpyrrolidine by the procedure described in Example 87, Step 2, yield 9195.

F) Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of Example 1, except that the pH is adjusted to 4-5, obtaining the title acid in a yield of 9995. High resolution MS calcd. for (SzoNaoSiMa3O55-NO 698.24609, found 698.24572. in Example 114: 4-(2-(1-benzhydryl-5-chloro-2-12-(2-(2-methylpiperidin-1-ylluethanesulfonylamino|ethyl) -1H-indole-3-yl)ethoxy|benzoic acid

Step 1: This compound is prepared from the intermediate of Example 87, Step 1 and 2-methylpiperidine by the procedure described in Example 87, Step 2, yield 9195. 65 Step 2: The intermediate, which is an ester, is hydrolyzed according to Step 8 of Example 1, except that the pH is adjusted to 4-5, obtaining the title acid with a yield

9695. MS high-resolution computing. for (SloNaSIMzO55-NI 712.26174, found 712.26113.

Example 115: 4-(2-(1-benzhydryl-5-chloro-2-12-(2-(2,5-dimethylpyrrolidin-1-ylluethanesulfonylamino|ethyl)-1H-indol-3-yl)ethoxy|benzoin acid

Step 1: This compound was prepared from the intermediate of Example 87, Step 1 and 2,5-dimethylpyrrolidine by the procedure described in Example 87, Step 2, yield 8195.

Step 2: The ester intermediate is hydrolyzed in accordance with step 8 of example 1, except that the pH is adjusted to 4-5 to give the title acid in a yield of 70 C69o. MS of high resolution calculations. for |ShoNaaSIMzO55-H) 712.26174, found 712.26114.

Example 116: 4-(2-71-benzhydryl-5-chloro-2-(2-(2-thiomorpholine-4-ylethanesulfonylamino)ethyl/|-1H-indol-3-ilyethoxy)benzoic acid

Step 1: This compound was prepared from the intermediate of Example 87, Step 1 and thiomorpholine by the procedure described in Example 87, Step 2, yield 93905.

Step 2: The ester intermediate is hydrolyzed in accordance with step 8 of Example 1, except that the pH is adjusted to 4-5 to give the title acid in a yield of 9095. High resolution MS calcd. for (SzvaNaoSIMAOv552-NO 716.20251, found 716.20217.

Example 117: 4-(2-71-benzhydryl-5-chloro-2-(2-(2-piperidin-1-ylethanesulfonylamino)ethyl|-1H-indol-3-yl)ethoxy)benzoic acid

Step 1: This compound was prepared from the intermediate of Example 87, Step 1 and piperidine by the procedure described in Example 87, Step 2, in a yield of 99905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, except that the pH is adjusted to 4-5, obtaining the acid indicated in the title with a yield of c ov 327. MS of high resolution calculations. for |SzoNaoSIM3O5Z2-H) 698.24609, found 698.24570.

Example 118: (8) 4-2-P1-benzhydryl-5-chloro-2-(2-o-tolylsulfanylmethane-sulfonylaminoethyl)-1H-indol-3-yl|ethoxy)benzoic acid

Stage 1: To methyl 4-2-P1-benzhydryl-5-chloro-2-(2-H(chloromethyl)sulfonylisoamino)ethyl)-1H-indole-3-ylethoxy)benzoate, Example 81, Stage 1 , add o-thiocresol by the procedure described in Example 81, steps 2 and 3. The product is purified by preparative HPLC with a yield of 45905. -

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 "g of example 42, obtaining the acid indicated in the title with a yield of 9890. t/2 (M-1) 723.07. MS of high resolution calculations. for (Ca0NaUSIMoO55»o-NI 723.17596, found 723.17596. -

Example 119: 1-4-(2-71-benzhydryl-5-chloro-2-(2-(2-chlorophenylsulfanyl-methanesulfonylamino)ethyl/|-1H-indole-3-ilyethoxy)benzoic acid

Stage 1: To methyl 4-2-P1-benzhydryl-5-chloro-2-(2-H(chloromethyl)sulfonylamino)ethyl)-1H-indol-3-yl|ethoxy)benzoate, Example 81, stage 1, 2-chlorothiophenol is added by the procedure described "

In example 81, stage 2. The product is purified by preparative HPLC with a yield of 53905. shsh s Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed according to stage 8. of example 42, obtaining the acid indicated in the title with a yield of 100905. t/2 (M-1) 743.08. MS of high and resolution calculations. for |(SzoNaziSi»MoOB55o-NI 743.12134, found 743.12111.

Example 120: 4-(2-7-1-benzhydryl-5-chloro-2-(2-(2,6-dichlorophenylsulfanyl-methanesulfonylamino)ethyl|-1H-indol-3-yl)ethoxy)benz-I oleic acid

Stage 1: To methyl 4-2-P1-benzhydryl-5-chloro-2-(2-H(chloromethyl)sulfonyl-amino)ethyl)-1H-indol-3-yl|Iethoxy)benzoate, example 81, stage 1 , add 2,b-dichlorothiophenol by the procedure described in Example 81, stage 2. The product is purified by preparative HPLC with a yield of 15.790 and hydrolyzed with 5p Acid with a yield of 3790.

Ш- Stage 2: The intermediate compound, which is an ester, is hydrolyzed according to stage 8

He of example 42, obtaining the acid indicated in the title with a yield of 9890. t/2 (M-1) 776.93. MS of high resolution calculations. for |SzoNazzSizM2O55o-NI 777.08237, found 777.08205.

Example 121: 4-(2-71-benzhydryl-5-chloro-2-(2-(2,5-dimethoxyphenyl-sulfanylmethanesulfonylamino)ethyl/|-1H-indol-3-yl)ethoxy)benzoic acid

F) Stage 1: To methyl 4-2-P1-benzhydryl-5-chloro-2-(2-H(chloromethyl)sulfonyl amino)ethyl)-1H-indol-3-yl|Iethoxy)benzoate, example 81, stage 1, 2,5-dimethoxythiophenol is added by the procedure described in example 81, stage 2. The product is purified by flash chromatography using a mixture of 3590 in EtOAc/hexane to yield 65905.

Step 2: The ester intermediate is hydrolyzed according to step 8 of Example 42 to give the title acid in a yield of 99.5905. t/2 (M-1) 769.18. MS of high resolution calculations. for |C44NazoSIM2O755-NO 769.18144, found 769.18121.

Example 122: 65 4-(2-(1-benzhydryl-5-chloro-2-12-(2-(3-hydroxypyrrolidin-1-yl)ethanesulfonylamino|ethyl)-1H-indol-3-yl)ethoxy|benz oleic acid -58v-

Step 1: This compound was prepared from the intermediate of Example 87, Step 1 and 3-pyrrolidinol by the procedure described in Example 87, Step 2, in a yield of 9095 without column purification.

Step 2: The ester intermediate is hydrolyzed in accordance with step 8 of example 1, except that the pH is adjusted to 4-5 to give the title acid in a yield of 8490.t/2 (M-1) 699.99, MS of high resolution calculations. for |(SzvaNaoSIMzOv5-NI 700.22535, found 700.22490.

Example 123: 4-(2-(1-benzhydryl-5-chloro-2-12-(2-(4-hydroxypiperidin-1-yl)ethanesulfonylamino|ethyl)-1H-indol-3-yl)ethoxy|benz propyl acid 70 Step 1: This compound was prepared from the intermediate of Example 87, Step 1 and 4-hydroxypiperidine by the procedure described in Example 87, Step 2, yield 9595 without column purification.

Step 2: The ester intermediate is hydrolyzed in accordance with step 8 of example 1, except that the pH is adjusted to 4-5 to give the title acid in a yield of 4290.t/2 (M-1) 714.03. MS of high resolution calculations. for (SzoNa»SIMA3Ov65-NI 714.24100, found 714.24085.

Example 124: 4-(2-(1-benzhydryl-5-chloro-2-12-(2--2-dimethylaminomethylpiperidin-1-yl)ethanesulfonylamino|ethyl)-1H-indol-3-yl)ethoxy|benzoin acid

Step 1: This compound is prepared from the intermediate of example 87, step 1 and

K-(2-piperidylmethyl)dimethylamine by the procedure described in example 87, stage 2, with a yield of 9095 without purification of 2o on the column.

Step 2: The ester intermediate is hydrolyzed in accordance with step 8 of example 1, except that the pH is adjusted to 4-5 to give the title acid in a yield of 7190.t/2 (M-1) 754.94. MS of high resolution calculations. for |C2NaoSIMAO55-NI 755.30394, found 755.30344.

Example 125: 4-(2-7-11-benzhydryl-5-chloro-2-(2-(2-imidazol-1-ylethanesulfonylamino)ethyl/|-1H-indole-3-ylethoxy)benzoic acid

Step 1: This compound is prepared in a yield of 87905 from the intermediate of Example 87, Step 1 and imidazole i) by the procedure described in Example 87, Step 2, except that the substance is heated at 1209 for 4.5 days.

Stage 2: The intermediate compound, which is an ester, is hydrolyzed according to stage 8 Ha

From example 1, except that the pH is adjusted to 4-5, obtaining the acid indicated in the title with a yield of 6090. t/2 (M-1) 681.17. MS of high resolution calculations. for (C57Na5SIMAO55-NO 681.19439, found 681.19409. -

Example 126: "I 4-(3-P1-benzhydryl-5-chloro-2-(2-X(2,6-difluorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Ipropyl)benzoic acid

Stage 1: Intermediate sulfonyl chloride is obtained from 2,6-difluorobenzyl bromide by the procedure of example 18, -

From stage 1-2 with quantitative output. uh-

Stage 2: The complex methyl ether is obtained from sulfonyl chloride and methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)ubenzoate (stage b, example 42 ) by the procedure of example 1, stage 7 with output 53905.

Stage 3: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9295. n/z: (M-I) 711.2. MS of high resolution in c calculations. for (С4а0Нз5СПР2М20,-НИ 711.19013, found 711.18965. and Example 127: «» 4-(3-P1-benzhydryl-2-(2-1(3,4-dichlorobenzyl)sulfonyl|amino)zetyl)- 1H-indol-3-yl|Ipropyl)benzoic acid

Step 1: The 2-methylindole is treated with the intermediate of Example 42, Step 1, by the procedure of Example 42, Step 2, to give the desired product in 8895 yield. -and Step 2: The product from the previous step is alkylated with benzhydryl bromide by the procedure of Example 42, Step 3, to give the product with a yield of 6590. - Step C: The product from the previous step is oxidized using the conditions indicated in Example 42, step 4, to give the desired 2-formylindole with a yield of 8595.

Step 4: The indole from the previous step is subjected to the nitroaldol conditions described in Example 42, Step 6. - Step 5: The vinyl nitro compound from the previous step is reduced under the conditions described in Example 42, Step 6 to give the desired aminoindole in a yield of 3995.

Step 6: The amine from step 5 is treated with (3,4-dichlorophenyl)methyl|sulfonyl chloride by the procedure of Example 43, step 7, to give 10095 g of the desired product.

Stage 7: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 42, obtaining the acid indicated in the title with a yield of 2495. MS high-resolution calculations. for iF) ISloNzeSIM2O,-NO 709.1700, found 709.16951. Example 128: 4-I3-(1-Benzyl-2-2-((benzylsulfonyl)amino|ethyl)-1H-indol-3-yl)/propyl|IbSenzoic acid

Step 1: This compound was prepared from the intermediate of Example 127, Step 5 and d-toluenesulfonyl chloride 6o by the procedure of Example 43, Step 7, to give the desired product 83965.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 42, obtaining the acid indicated in the title with a yield of 9595. MS high-resolution calculations. for

ISloNzvMm2O,5-NI 641.24795, found 641.24761.

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The correspondingly substituted halogenated amine reacts with trifluoroacetic anhydride to give an intermediate that can be treated with Ra! catalyst in the presence of a base such as triethylamine, Si! and a suitable alkyne

HF) on heating, giving the desired intermediate indole. The primary alcohol is protected as a silyl ether using a silyl chloride such as tert-butyldiphenylsilyl chloride and a base such as imidazole. The protected indole is then treated with oxalyl chloride followed by methanol to give the desired complex oxalate ester, which can be alkylated with a suitable base such as cesium carbonate in acetonitrile and halide at reflux at 60°C. The oxalate can then be reduced with a suitable reducing agent such as borane.

The resulting primary alcohol is converted into a halide using, for example, SVg; and a phosphine, which can then be a nucleophile such as thiophenol. The resulting thioether can be oxidized with a variety of oxidizing agents, including oxone and TAP/YMO. The resulting sulfone can be deprotected with a fluorine source such as TVAE, CzE, or HE. The resulting alcohol can be converted to a bo halide or mesylate, for example, using methanesulfonyl chloride and an organic base, which can then be replaced by sodium azide in DMF. The resulting alkyl azide can be regenerated under the action of triphenylphosphine and wet THF. The amine can be sulfonylated by sulfonyl chloride under biphasic conditions of Schott and Baumann, a mixture of aqueous bicarbonate and dichloromethane, or under anhydrous conditions involving a mixture of dichloromethane and organic

BASES such as M,M-diisopropylethylamine. The resulting intermediate is hydrolyzed using the base Mason, Kon, GION and a mixture of solvents including alcohol, water and tetrahydrofuran. In Examples 129-132 below, the synthesis was carried out by the EC method.

Example 129: 3-I4-(42-(/1-benzhydryl-5-chloro-2-(2-(2-chlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Hethylusulfonyl)phenyl|pr 7/0 opium acid

Stage 1: 2-bromo-4-chloroaniline (1.0 eq.) is dissolved in CH 25SiO (0.25 M), then triethylamine and trifluoroacetic anhydride (1.1 eq. each) are added. The resulting mixture is stirred at room temperature for 1 hour. Then the solvent is removed from the reaction mixture and the residue is purified by flash chromatography with dichloromethane as eluent, obtaining the desired product with a yield of 9790. t/2 (M-H)- 300.0. 9 Stage 2: M-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroacetamide (stage 1, 1.O0eq.) is mixed with 3-butyn-1-ol (2.Eq.), dichlorobis( triphenylphosphine) palladium (I) (2.59 seq.), triethylamine (3Z, Equiv.), Si! (59 sec.) in DMF (0.2M) in a hermetic vessel in an atmosphere of M" and heated at 1202C for 4 hours. Then the reaction mixture is diluted with ethyl acetate, washed with a saturated salt solution and dried over Ma 2503. Next, the solvent is evaporated and the residue is purified by flash column chromatography using a mixture of 2906 MEeOH/CH 2Si", obtaining the described product (A) with a yield of 67905. t/2 (M-H) 194.09.

Step 3: 2-(5-chloro-1H-indol-2-yl)ethanol (Step 2, 1.0 eq.) and imidazole (2.0 eq.) are dissolved in DMF (0.3 M) at room temperature with stirring, after which tert-butylchlorodiphenylsilane (1.2 eq.) is added.

The resulting mixture was kept at room temperature overnight, after which it was quenched with He 25 saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase is washed with water, a saturated salt solution and dried over Na»5O). The solvent is removed and the residue is purified on a column with

СНоСИ» as an eluent, obtaining the desired product in the form of a brown resin with a yield of 9095. t/2 (M-Н) 433.0.

Stage 4: 2-(Jagret-butyldiphenyl)silyl|oxy)ethyl)-bchloro-1H-indole (stage C, 1.0 eq.) is dissolved in ether (0.4M) and the solution is cooled to 02. To the cold solution from the previous stage with vigorous stirring EM 30 add oxalyl chloride (1.2 equiv.). The reaction mixture is kept at 02C for 1 hour, after which add ch

EUN, followed by Mei3. The resulting mixture is then diluted with an additional amount of EN, after which it is poured into water. The organic phase is washed with a saturated salt solution, dried over

Ma»5zO,, is concentrated, obtaining the desired product in the form of a solid yellowish substance with a yield of 70905. t/7 i- (M-H) 533.0. 3o Step 5: Ethyl (|2-(tert-butyl(idiphenyl)silyl|oxyethyl)-5-chloro-1H-indol-3-yl|| oxo)acetate (step 4, 1 in equiv.), RP2CHHg (1 .5 equiv.) and C8v»CO»Z (1.5 equiv.) are mixed in dry acetonitrile (0.1M). The mixture is refluxed with stirring for 2 hours. The reaction mixture is cooled to room temperature, water is added, and EIAs is extracted. The organic phase is concentrated and the residue is purified on a column with du CHNOCl as an eluent, obtaining the desired product in the form of a yellow-brown resin with a yield of 4595. t/2 (МН) 7 with 701.3. c Step 6: Ethyl (|1-benzhydryl-2-(tert-butyl(idiphenyl)silyl|oxy)ethyl)-5-chloro-1H-indol-3-yl(oxo)acetate :c" (step 5, Teq .) is dissolved in THF (0.1 M), then VN z.Me»5 (2 M in THF) (2 equiv.) is added. The resulting mixture is refluxed with stirring overnight in an atmosphere of Mo. The reaction mixture is cooled to room temperature, then slowly quenched with NaOH. They are washed with a saturated salt solution, -1, followed by the extraction of EIHUAs. Removal of the solvent gives the desired product in a yield of 6590. t/2 (MAN) "645.0.

Step 7: 2-(1-benzhydryl-2-(tert-butyldiphenyl)silyl|oxy)ethyl)-5-chloro-5-indol-3-yl|ethanol (step 6, and 1 equiv.) is dissolved in CH- SI" (0.08M), then add 1,3-bis(diphenylphosphino)propane (ORPP, 0.75 eq.). Their solution is cooled to 09 in an atmosphere of Mo, then added with stirring SVg; (1.25 eq.). Stirring is continued for 2 hours until the temperature of the reaction mixture returns to room temperature.

Sh- The solvent is removed and the residue is purified by passing it through a short column with CH 2Si" as an eluent,

Kz obtaining the desired product in quantitative yield, t/2 (MAN) 708.0.

Step 8: 1-Benzhydryl-3-(2-bromomethyl)-2-(tert-butyl(idiphenyl)silyl|oxy)ethyl)-5-chloro-1H-indole (step 7, Leq.) is mixed with methyl-3 -(4-mercaptolphenyl)propionate (1.5 eq.) and CaSO 4 (1.5 eq.) in DMF (0.1 M). Mixture,

The resulting product is stirred at room temperature under Mo for 2 h, then water is added, followed by extraction with ethyl acetate, washing with saturated salt solution, and column purification (CH 2 SiO 2 as eluent) to give the desired product with a yield of 8095 as a brownish solid resin, t/7 ime) (MeAN)" 823.0.

Step 9: Methyl bo 3-ID-((2-(1-benzhydryl-2-(tert-butyldiphenyl)silyl|oxy)ethyl)-5-chloro-1H-indol-3-ylylethyl)sulfanyl)phenyl|prop anoate (step 8, Eq.) is dissolved in acetonitrile (0.1 M), then molecular sieve (powder, 4A) and 4-methylmorpholine-M-oxide (MMO) (4 eq.) are added under Mo atmosphere. After 5 minutes H-RgAMKyO is added to the mixture; (TRAR) (5 Seq.). The resulting mixture is heated to 402C with stirring and kept for 1.5 hours.

After removing the solvent, the residue is purified on a column using SNeoSi», then a mixture of 196 EUAs/CH»oSi» as eluent, obtaining the desired product in the form of a white foam with a yield of 4495. t/2 (MAN) 855.1.

Stage 10: Methyl

3-(4-42-(/1-benzhydryl-2-(tert-butyldiphenyl)silyl|oxy)ethyl)-5-chloro-1H-indol-3-yl|ethoxy)phenyl)propanoate (stage 9, Eq. ) is dissolved in THF (0.1 M) and cooled to 0 C, after which nVi ME (1 M in THF) (1.2 equiv.) is added. The resulting mixture is stirred at 09C for 5 minutes, then heated to room temperature and stirred for 30 minutes. Remove the solvent. The residue is purified on a column with a mixture

EUAs/СНе-СИ" (from 1:9 to 1:4) as an eluent, obtaining the described intermediate compound in the form of a white foam with a yield of 9095. t/2 (MAN) 616.20.

Step 11: Methyl 3-N4-12-(/1-benzhydryl-5-chloro-2-(hydroxyethyl)-1H-indol-3-yl|ethyl)sulfonyl)phenyl|Ipropanoate (Step 10, eq.) 70 in dichloromethane (0.02M) is treated at 02С with a mixture of Meso-si (2 eq.) and EBM (2.5 eq.) and stirred for 1 hour. The ice bath is removed and the reaction mixture is stirred for another 1 hour at room temperature, after which it is diluted with СНоСи», washed with NaCl, a saturated salt solution and dried over Mа»5О. Evaporate the solvent to give the desired product in quantitative yield, t/72 (MAN) 695.0.

Step 12: Methyl 75. 3-(4-C2-(1-Benzhydryl-5-chloro-2-22-(methylsulfonyl)oxy|ethyl)-1H-indol-3-yl)lethyl|Isulfonylphenyl)propanoate (Step 11 , 1.0 equiv.) are dissolved in DMF (0.03M) and treated with Mam from (3.0 equiv.). The resulting mixture is heated to 60°C and stirred for 2 hours, then water is added, extracted with ethyl acetate, washed with saturated salt solution and dried over NaCl. Evaporation of the solvent gave the desired product in quantitative yield, pt/2 (MAN)" 641.1.

Step 13: Methyl 3-I4-(12-(2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indole-3-ylethylusulfonyl)phenyl|Ipropanoate (step 13, eq.) is dissolved in THF ( . obtaining the described product with a yield of 7190. t/72 (MAN) 615.2. o

Step 14: Methyl 3-I4-(12-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethyl)sulfonyl)phenyl|Ipropanoate (Step 12, eq.) and (3,4-dichlorobenzyl)sulfonyl chloride (1.1 eq.) are dissolved in CH 2Si" (0.1M) at room temperature, then an aqueous solution of Ma"CO3 is added under stirring. Stirring continues for 2 hours. Then the organic phase is separated, washed with a saturated salt solution, dried over NaCl). The solvent is evaporated, and the residue is purified on a column using a mixture of 296 MeOH:CH2Cl2 as an eluent to give the desired product with a yield of 8595 as a white solid, pt/2 (M-H) 834.9.

Stage 15: Methyl c. 3-I4-(42-(/1-benzhydryl-5-chloro-2-(2-1(3,4-dichlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-ylylethyl)isulfonyl)phenyl |propanoate (step 14, 1.0 eq.) is dissolved in a mixture of THF:Meon (1:1) (0.1M), then added yin Maon. The mixture is stirred overnight at room temperature. The solvent is removed and the residue is dissolved in water, obtaining an alkaline solution, which is neutralized with a dilute solution of NSI to precipitate the product. The solid was collected by filtration, washed with water, washed with hexane, then dried to give the "desired product in 867 yield". MS of high resolution calculations. for |С 44Н37СиИзМ»Ов5оН| 823.12314, 73 s found 823.12292.

Example 130: ; t 3-(4-4C2-(1-benzhydryl-2-2-(benzylsulfonyl)amino|ethyl)-5-chloro-1H-indol-3-ylethyl|sulfonyl)uphenyl)propionic acid

Step 1: The intermediate of Example 129, Step 13 is treated with a-toluenesulfonyl chloride by Procedure -1 of Example 129, Step 14 to give the desired compound in a yield of 9490.

Step 2: The intermediate from the previous step is treated with Mahon by the procedure described in Example 129, step 15, to give the desired acid in a yield of 9295. High resolution MS calcd. for |C 44NzoSIM»Ov52 NOT their 755.20109, found 755.20201. 20 Example 131: and 3-I4-(42-(/1-benzhydryl-5-chloro-2-(2-1(2,6-difluorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-ylylethyl) isulfonyl)pheny kz l|propionic acid

Step 1: The intermediate of Example 129, Step 13 is treated with (2,6-difluorophenyl)methanesulfonyl chloride by the procedure of Example 129, Step 14 to give the desired compound of

EXIT 4290.

Step 2: The intermediate from the previous step is treated with Mahon using the procedure described in Example 129, (F. step 15) to give the desired acid in a yield of 8395. High Resolution MS calcd for

GI ISli On SIR»MoOv5o NO 791.18224, found 791.18257.

Example 132: in 3-14-(42-(/1-benzhydryl-5-chloro-2-(2-1(2-fluorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|1ethylusulfonyl)phenyl |pr opionic acid

Step 1: The intermediate of Example 129, Step 13 was treated with (2-fluorophenyl)methanesulfonyl chloride by the procedure of Example 129, Step 14 to give the desired compound in yield 4296.

Step 2: The intermediate from the previous step was treated with Mahon by the procedure described in Example 129, 65 step 15, to give the desired acid in a yield of 8695. High resolution MS calcd. for

ISl1NzvSIEM2O 652 NO 773.19166, found 773.19213.

Method o 10 Я 15 On НН НН НН шчу ОБил лу» 20 нки ши я ШЮ шин 25 t ши ша ше NN НА ш о и-

The intermediate of method E can be alkylated in the C3 position with aldehydes or the corresponding acetals in the presence of Lewis or Brønsted acids such as boron trifluoride etherate or trifluoroacetic acid. The indole nitrogen can then be alkylated by treatment with a strong base such as sodium bis(trimethylsilyl)amide, n-Vygium, 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 be oxidized with various oxidizing agents, including oxon and TPAR/MMO. The resulting sulfone can be deprotected by a fluorine source such as

In and and

FACE, SzE or NOT. The resulting alcohol can be converted to a halide or mesylate, for example, using methanesulfonyl chloride and an organic base, which can then be replaced with sodium azide in DMF. :z» The alkylazide obtained as a result can be restored under the action of triphenylphosphine and wet THF. The amine can be sulfonylated by sulfonyl chloride under biphasic conditions of Schott and Baumann, a mixture of aqueous bicarbonate and dichloromethane, or under anhydrous conditions involving a mixture of dichloromethane and an organic base such as 15 M,M-diisopropylethylamine. The resulting intermediate is hydrolyzed using the base, Mahon,

KOH, PON, and a mixture of solvents including alcohol, water, and tetrahydrofuran. In the following examples 133, -| 135-138 and 140-141 synthesis was carried out according to method 0. 1" Example 133: 3-I4-(42-(/1-benzhydryl-5-chloro-2-(2-(2-chlorobenzyl)sulfonyl|amino)ethyl )-1H-indol-3-yl|Iethylusulfonyl)phenyl|pr -i 50 opionic acid "from Stage 1: Ethyl 4-(2-oxoethyl)sulfanyl|propanoate (Example 129, stage 3, 4.2 eq.) is added to of a solution containing 2-(tert-butyl(idiphenyl)silyl|oxyethyl)-5-chloro-1H-indole (Teq.), TFO (Teq.), and 1,2-dichloroethane (0.1M) at 02С in Mo atmosphere. EBZIN (12 eq.) is then added, the reaction mixture is allowed to warm to room temperature and stirred overnight. The reaction mixture is quenched with aqueous Manso, extracted with EtOAc, washed with saturated brine, and dried over sodium sulfate. Purified on a silica gel column, (F) using a mixture of 1:5 E(JAc/hexane as an eluent. Ethyl 4-(12-(2-(2-N-tert-butyldiphenyl)silyl|oxy) is obtained

He ethyl)-5-chloro-1H-indol-3-yl|ethyl)usulfanyl)propanoate (yellow oily substance) with a yield of 79905.

Step 2: Ethyl 4-(12-(2-(2-tert-butyl(idiphenyl)silyl|oxyethyl)-5-chloro-1H-indol-3-yl|ethyl)sulfanyl)propanoate (Eq.) is added to suspension of Man (1.Eq.) in DMF (0.38M) at 02С in an atmosphere of Mo. After 30 minutes, RP2SNVH is added and the reaction mixture is heated to room temperature. After 2.5 hours, the reaction mixture is quenched with MNACI (aq.), extracted with a mixture of EtOAc/EBO, washed with water and saturated salt solution, and dried over sodium sulfate. Purify on a silica gel column using a 1:66 EAs/hexane mixture. Ethyl 65 3-I4-(12-(1-benzhydryl-2-(2-tert-butyldiphenyl)silyl|oxy)ethyl)-5-chloro-1H-indol-3-yl|ethylsulfanyl)phenyl|propanoate ( yellow resin) with a yield of 4296.

Stage C: To a solution/suspension containing ethyl 3-14-(12-(1-benzhydryl-2-(2-tert-butyldiphenyl)silyl|oxy)ethyl)-5-chloro-1H-indol-3-yl |iethylsulfanyl)phenyl|propanoate (Teq.), acrylonitrile (0.1M) and molecular sieves (1g/mmol propanoate) in an atmosphere of Mo add MMO (Dec.). After 10 minutes, TRAP (0.05 eq.) was added and the mixture was heated to 402C. After 2 hours, the reaction mixture is cooled and filtered, and the filtrate is collected. Purify on a silica gel column using a 1:4 mixture

EtOAc/hexane. Ethyl 3-14-(12-(1-benzhydryl-2-(2-tert-butyldiphenyl)silyl|oxy)ethyl)-5-chloro-1H-indole-3-yl|ethylsulfonyl)phenyl|propanoate (solid) is obtained white substance) with a yield of 86905. 70 Stage 4: To a solution of ethyl 3-I4-(42-(1-benzhydryl-2-(2-tert-butyldiphenyl)silyl|oxy)ethyl)-5-chloro-1H-indole- To 3-yl|ethylsulfonyl)phenyl propanoate (Eq.) and THF (0.1 M) at 02С under Mo atmosphere add tetrabutylammonium fluoride (1 M in THF) (1.2 eq.).

The reaction mixture is heated to room temperature and quenched with MNASI (aq.) after 30 minutes. They extract

EtOAc, washed with saturated salt solution and dried over sodium sulfate. Purify on a 75 silica gel column using a 1:9 EtOAc/CH2Cl mixture. Ethyl 3-14-(42-(/1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indole-3-ylphenylethylsulfonyl)phenyl]propanoate (white solid) was obtained in a yield of 8890.

Stage 5: To a solution of ethyl 3-14-(2-P1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-ylethyl)usulfonyl)phenyl|propanoate (Teq.) in CHClCl, ( . After 1 hour, the reaction mixture is heated to room temperature. After another hour, water is added, СНоСи is extracted, washed with a saturated salt solution and dried over sodium sulfate. The solvent was removed to give ethyl 3-(4-4C2-(1-benzhydryl-5-chloro-2-2-(methylsulfonyl)oxy|ethyl)-1H-indol-3Z-ylethyl|sulfonyl)phenyl)propanoate (white solid) ) with output 98905. p

Stage 6: Ethyl o 3-(4-4C2-(1-benzhydryl-5-chloro-2-2-(methylsulfonyl)oxy|ethyl)-1H-indol-3Z-ylethyl|sulfonyl)phenyl)propanoate (Eq.) , sodium azide (aq.), and DMF (0.05M) are mixed in an atmosphere of Mo and heated to 602С. After 1 hour, the reaction mixture is cooled and water is added. Extracted with a mixture of EFAS/EBO, washed with water and saturated salt solution and dried over sodium sulfate. The solvent was removed to give ethyl c 3-14-(42-(2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethyl)/sulfonyl)phenyl|propanoate (solid m clear -brown substance) with a yield of 9690.

Stage 7: Ethyl 3-I4-(2-(2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethyl)sulfonyl)phenyl|Ipropanoate « (Tech.), PP (deposited on the polymer) (1, Eq.) and THF (0.1 M) are mixed in an atmosphere of Mo. After 3 days, add water m (Iml/lmmol propanoate) and the reaction mixture is stirred overnight. Filter and collect the filtrate.

Purify on a column with silica gel using a mixture of 295 MeOH in СНоСИ». Ethyl 3-I4-(12-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethyl)sulfonyl)phenyl|Ipropanoate (light brown solid) is obtained with an output of 6590.

Stage 8: To the mixture of ethyl 3-I4-(12-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethyl)sulfonyl)phenyl|Ipropanoate (Teq.) , CHClCl (0.08M), water (1 mL/L/mL CHCl), and MgSOCl (2.5 eq.) add (2-chlorobenzyl)sulfonyl chloride (2.2 eq.). After 2-s hours, (2-chlorobenzyl)sulfonyl chloride (1.1 eq.) is added. After another 1.5 hours, the organic layer is separated, washed with saturated salt solution and dried over sodium sulfate. Purify on a "preparative silica gel plate using a mixture of 2950 MeonH in СНоБСи". Ethyl 3-14-(42-(/1-benzhydryl-5-chloro-2-(2-(2-chlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Hethylusulfonyl)phenyl|propanoate is obtained (light yellow resin) with a yield of 75905. - and Stage 9: Ethyl -1 3-I4-(42-(/1-benzhydryl-5-chloro-2-(2-(2-chlorobenzyl)sulfonyl|amino)ethyl )-1H-indol-3-yl|Hethylusulfonyl)phenyl|propanoate (Eq.), THF (01M), Meon (1ml/1ml THF) and Mahon (n) (11eq) were stirred together overnight. Solvents are removed and the resulting residue is placed in water. The solution is acidified with NCI and -1 50, the precipitate formed is collected by filtration. Obtain 3-14-(42-(/1-benzhydryl-5-chloro-2-(2-(2-chlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Hethylusulfonyl)phenyl|pr

I» opionic acid (solid light-curic substance) with a yield of 8395. MS of high resolution calculations. for

ISZENZESIMAZO,'ANI 789.16211, found 789.16311.

Method N

F) name) 60 b5

Gay

That she - pera nick Monte and odetetuy in sch

An appropriately substituted indole-2-carboxylate can be reduced with a suitable reducing agent, such as lithium aluminum hydride, aira! etc. and then the resulting alcohol can be oxidized to M 2-formylindole using MpO" under Swern oxidation conditions or other oxidizing agents. The indole nitrogen can then be alkylated by treatment with a strong base such as sodium bis(trimethylsilyl)amide, n-Vi, sodium hydride or potassium hydride in a solvent such as DMF, DMSO or THF, followed by exposure to a suitable M halide. The aldehyde is then treated with nitromethane and a base such as ammonium acetate to give the intermediate 35Vinyl nitro compound, which can be reduced with a variety of agents such as lithium aluminum hydride or y-7p(Na) amalgam in NSI. The resulting amine is sulfonylated using sulfonyl chloride under Schott and Baumann biphasic conditions or under anhydrous conditions with an organic base. Treatment of the resulting sulfonamide with a strong base, such as sodium bis(trimethylsilyl)amide, n-Bi, sodium hydride, or potassium hydride in a solvent such as DMF, DMSO, or THF, followed by exposure to a silyl chloride such as 40 tert- butyldimethylsilyl chloride, gives the protected sulfonamide. This substance can be formulated according to SZ, Z c using standard Vilsmeyer conditions, a mixture of ROSIZ/DMF. The thus obtained 3-formylindole is reductively aminated using a suitable amine, a reducing agent such as sodium triacetoxyborohydride, and an acid such as glacial acetic acid. The resulting intermediate compound is hydrolyzed using the base, Mahon, con, PON, and a mixture of solvents including alcohol, water, and tetrahydrofuran. Example 134 45 synthesized according to the method of N. sh- Example 134: 4-(4(1-benzhydryl-2-2-(benzylsulfonyl)amino|ethyl)-5-chloro-1H-indol-3-yl)-I methyl| amino)methyl)benzoic acid

Stage 1: Ethyl ether of 5-chloro-1H-indole-2-carboxylic acid (Eq.) is dissolved in THF (0.4M), purged with nitrogen, then the mixture is cooled to 02C and lithium aluminum hydride is slowly added (Eq. 1M solution in THF). -I 20 The reaction mixture is allowed to slowly warm to room temperature and stirred until TLC analysis shows completion of the reaction. After cooling the flask to 0 °C, slowly add Mahon (bOml Zn solution) and stir the reaction mixture until two layers are formed. 1. The layers are separated, the aqueous layer is extracted 2 times with ethyl acetate, the combined organic layers are washed with a saturated salt solution, then dried over magnesium sulfate and concentrated, obtaining the desired alcohol, which is used crudely in the next stage.

Stage 2: The product from the previous stage (Solution) is dissolved in THF (0.5M), treated with manganese dioxide

HF) (Seq.) and stirred for 1.5 hours until the TLC analysis shows the completion of the reaction. The reaction mixture was then filtered through celite, dried over magnesium sulfate, and concentrated to give the desired crude aldehyde in a yield of 82965.

Stage 3: To the indole from the previous stage (1.0 eq.) in DMF (0.36 M) at 2592C, ManN (1.2 eq., 6090 bo dispersion in oil) is added and the brown solution is stirred at a temperature from 0 to -52C for 1 hour ., then bromodiphenylmethane (1.1 eq.) is added and the reaction mixture is then stirred overnight. The reaction mixture was then quenched with water, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and purified by column chromatography to give 6095 g of the desired product. b Stage 4: To the above aldehyde (1.00 eq.) in SNUMO" (0.075 M) is added ammonium acetate (ZCheq.) and the resulting mixture is refluxed overnight. The reaction mixture is concentrated to a small volume, then diluted with EtOAc and washed with saturated salt solution. The aqueous phase is extracted

EUAs. The combined organic extracts are washed with saturated salt solution, dried over sodium sulfate, concentrated and purified by column chromatography to the desired nitroolefin (yield 51905).

Stage 5: Zinc dust (20 equiv.) is suspended in 596 aqueous solution of NSI (8M 2p/595 NS). Naoshi is added to this mixture" (0.2 century). The mixture is shaken for 10 minutes, the aqueous phase is decanted and replaced with fresh 5905 NS, the mixture is shaken again for two minutes. and the aqueous phase is removed. The zinc-mercury amalgam thus obtained is then added to a mixture of nitroolefin (1.0 eq.) and concentrated NCI (8 eq.) in THF (0.04 M nitroolefin/THF). The mixture is gently boiled under reflux for 1 hour. The formation of /o0 product is monitored by TLC. The mixture is cooled to room temperature and the solid is removed by filtration through celite. Concentrated MH OH is added to the solution phase and the mixture is concentrated on a rotary evaporator. The residue is dissolved in CH 2Si" and concentrated MNAOH. The aqueous phase is extracted

СНоСИ», the organic phase is washed with a saturated salt solution, dried over sodium sulfate and concentrated, obtaining the desired crude amine (10095), which is used in the next step without purification.

Stage 7: To the amine from the previous stage (1.0 eq.) and saturated Manso with (0.14 M) in SNSI" (0.07 M) is added

A-toluenesulfonyl chloride (1, Equiv.). After 1 hour, the mixture is poured into a saturated solution of sodium bicarbonate and extracted with СНоСИ». The combined organic phase is washed with saturated salt solution, dried over sodium sulfate and purified by column chromatography (gradient elution using a mixture of 1090

EAs-hexanes -» 2095 EAs-hexanes), obtaining 4095 of the desired sulfonamide.

Step 8: The sulfonamide from the previous step is dissolved in DMF (0.5M) under nitrogen, cooled to 02C, treated with sodium hydride (1.05 eq. 6095 oil dispersion), stirred for 15 minutes to ensure anion generation, treated with tert-butyldimethylsilyl chloride (1.2 eq.) and then stirred for two hours at 0 2C, after which TLC analysis shows that the reaction is complete. The reaction mixture is worked up by partitioning the mixture between 1/2 of a saturated solution of ammonium chloride and ethyl acetate, extracting the aqueous layers with ethyl acetate (2x), washing the combined organic layers with saturated salt solution (1x), drying over magnesium sulfate, and concentrating to give the desired crude protected sulfonamide in i) quantitative yield.

Stage 9: Phosphorus oxychloride (1.2 equiv.) is added to DMF (-ml), these reagents are stirred for 10 minutes and then a solution of indole (equiv.) in DMF (0.8M) from the previous stage is added. Obtained as a result of SU

The red reaction mixture is stirred for 4 hours, diluted with water, then the pH is adjusted to 8 (the total volume of water added is approximately 95 of the DMF added initially), then the reaction mixture is boiled - under reflux for 2 hours and, finally, cooled, extracted with dichloromethane , aqueous "The first layer is extracted with dichloromethane (2x), the combined organic layers are washed with a saturated salt solution (1x), dried over magnesium sulfate and concentrated, obtaining the crude aldehyde, which is used without further purification, with a yield of 75905. -

Stage 10: 4-aminomethylbenzoic acid methyl ether (1.2 equiv.), sodium triacetoxyborohydride (1. equiv.) and acetic acid (glacial, 1.bEq.) are added to the aldehyde from the previous stage (Tekv-» in THF (12M) The reaction mixture is stirred overnight, then treated by adding a saturated solution of sodium bicarbonate and ethyl acetate, the layers are separated, the aqueous layer is extracted with dichloromethane (2x), the combined organic layers are washed with a saturated salt solution (1x), dried over magnesium sulfate, concentrated and purified and chromatographed to give the desired product in a yield of 3790. Step 11: The resulting ester is hydrolyzed by stirring THF (5 eq) in a mixture of THF (0.07 M) and enough MeOH to give a clear solution. control TLC (1090

Meon-СН»оСИ») after the disappearance of the original substance. The mixture is stirred at room temperature for 72 hours.

The mixture is concentrated, diluted with HO and acidified to pH 5 using 1M HO. The aqueous phase is extracted with EAs, the organic phase is washed with a saturated salt solution, dried over sodium sulfate and concentrated, obtaining the desired product with a yield of 8395. High resolution MS calcd. for |C z9NzvSIMzO,5-NI 7 676.20423, found 676.20397. Example 135: 4-1H12-(1-benzhydryl-2--2-(benzylsulfonyl)amino|ethyl)-5-chloro-1H-indol-3-yl)ethyl| sulfonyl) benzoic acid and Stage 1: To a solution containing tert-butyldiphenylchlorosilane (1.2 equiv.), imidazole (2. equiv.) and DMF (1.8M)

3 (under a nitrogen atmosphere), add 2-(5-chloro-1H-indol-2-yl)ethanol (Teq.). The reaction mixture is stirred overnight. Quench with ManNSO" (aq.) and extract with a mixture of EBO/EUAc. The organic layer is washed with water, saturated salt solution and dried over sodium sulfate. Purify on a column with silica gel and use a mixture of 1:4 hexane/CH2Cl2 as an eluent. 2-(tert-butyldiphenyl)silyl|oxy)ethyl)-5-chloro-1H-indole is obtained (yellow oily substance) with a yield of 985905. o Stage 2: To a solution containing 2-(tert-butyl(idiphenyl)silyl) |oxy)ethyl)-5-chloro-1H-indole (Eq.), TFO co (Eq.) and 1,2-dichloroethane (0.1M), at 09C and in an atmosphere of Mo add methyl 4-((2- oxoethyl)sulfanyl|benzoate (3.7 eq.). Then EBb5iN (12 eq.) was added, the reaction mixture was allowed to warm to room temperature and stirred overnight. Quenched with MnSO" (aq.), extracted with EtOAc, washed with brine and dried over sodium sulfate Purified on a silica gel column using a 1:5 mixture of E(H2Ac/hexane as eluent. Methyl 4-(12-(2-(2-tert-butyl(idiphenyl)silyl|oxyethyl)-5-chloro is obtained -1H-indol-3-yl|ethyl)sulfanyl) benzoate (yellow solid) in yield 79905. 65 Step C: Methyl 4-(12-(2-(2-tert-butyl(idiphenyl)silyl|oxyethyl)- 5-Chloro-1H-indol-3-yl|hethyl)sulfanyl)benzoate (Eq.) is added to a suspension of Mann (1.1 eq.) in DMF (0.37M) at 09С and in the atmosphere Mo. After 30 minutes, RP2SNVHg (1 equiv.) was added and the reaction mixture was heated to room temperature. After 3 hours, the reaction mixture is quenched with MH Ace (aq), extracted with a mixture of E(Ac/EBBO), washed with water and saturated salt solution and dried over sodium sulfate. Purified on a silica gel column using a mixture of 1:5 E(Ac/hexane as eluent

Methyl 3-I4-(42-(1-benzhydryl-2-(2-tert-butyldiphenyl)silyl|oxy)ethyl)-5-chloro-1H-indol-3-ylethyl)sulfanyl)phenyl|benzoate is obtained (yellow resin ) with an output of 6590.

Stage 4: To a solution/suspension containing methyl 3-14-(42-(1-benzhydryl-2-(2-tert-butyldiphenyl)silyl|)oxy)ethyl)-5-chloro-1H-indole-3- il|Iethylsulfanil) 70. phenyl|benzoate (Teq.), acrylonitrile (0.1M) and molecular sieves (1 g/mmol of benzoate), in an atmosphere of Mo add MMO (Dec.). After 10 minutes, TRAP (0.12 eq.) was added and the mixture was heated to 402. After 1.5 hours, the reaction mixture was cooled, filtered, and the filtrate was collected. Purify on a silica gel column using a 1:5 mixture

EtOAc/hexane. Methyl 3-14-(42-(/1-benzhydryl-2-(2-tert-butyldiphenyl)silyl|oxyethyl)-5-chloro-1H-indol-3-yl 75 ethyl)sulfonyl)phenyl|benzoate (solid) is obtained white matter) with an output of 7190.

Stage 5: To the solution of methyl 3-I4-(42-(1-benzhydryl-2-(2-tert-butyldiphenyl)silyl|oxy)ethyl)-5-chloro-1H-indole-3-yl|ethylsulfonyl)phenyl benzoate (Eq.) in THF (0.1M) at 02С under Mo atmosphere, tetrabutylammonium fluoride (1M THF) (1.2 eq.) is added.

The reaction mixture is heated to room temperature and after 1 hour quenched with MN SI (aq). EMUAs is extracted, washed with a saturated salt solution and dried over sodium sulfate. Purify on a silica gel column using a 1:9 EtOAc/CH2Cl mixture. Methyl 3-14-(12-(/1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-ylethyl)sulfonyl)phenyl|benzoate (white solid) was obtained in a yield of 8690.

Stage 6: To a solution of methyl Ge 3-I4-(42-1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-ylethyl)usulfonyl)phenyl|benzoate (Teq.) in СНоСИ» o (0.02M) at 02C in a Mo atmosphere, add SNZO»-SI (2 equiv.) and EBM (2.5 equiv.). After 1 hour, the reaction mixture is heated to room temperature. After an additional hour, water is added, CH»-Si» is extracted, washed with saturated salt solution and dried over sodium sulfate. Remove the solvent, obtaining methyl 3-(4-Ch2-(1-benzhydryl-5-chloro-2-2-((methylsulfonyl)oxy|ethyl)-1H-indol-3-yl)ethyl|sulfonyl)phenyl)benzoate c (solid light yellow substance) with a yield of 9995. m

Stage 7. Methyl 3-(4-4C2-(1-benzhydryl-5-chloro-2-2-(methylsulfonyl)oxy|ethyl)-1H-indole-3-ylethyl|sulfonyl)phenyl)benzoate « (Tech.) , sodium azide (aq.) and DMF (0.05M) are combined in a Mo atmosphere and heated to 602С. After 1 hour, the reaction mixture is cooled and water is added. Extracted with a mixture of EFAS/EBO, washed with water, saturated salt solution and dried over sodium sulfate. The solvent was removed to give methyl i - 3-I4-(42-(2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-ylethylusulfonyl)phenyl|benzoate (light yellow solid) with output 99905.

Stage 8: Methyl 3-(4-(12-(2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|Hyethylusulfonyl)phenyl|benzoate " (TIeq.), PPHz ( 2 eq) and THF (0.1 M) were combined under Mo and stirred overnight. Water (1 mL/immol benzoate) was added and the reaction mixture was again stirred overnight. The solution was concentrated and purified on a silica gel column using mixture 3: 11 E(JudAc/hexane and then a mixture of 596 Meon in CH 2 Cl 1 ". Obtain h methyl 3-I4-(12-I(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl) |Iigthyl)sulfonyl)phenyl|benzoate (solid » light yellow substance) with a yield of 99905.

Stage 9: To the mixture of methyl 3-4-(42-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indole-3-ylethylsulfonyl)phenyl|benzoate (Tech.), СНоСИБ - (0 .08M), water (Iml/lml CHCl) and MgSbOz (2.5 eq.) add alpha-toluenesulfonyl chloride (2 eq.). After 2-1 hours, the organic layer is separated, washed with a saturated salt solution and dried over sodium sulfate.

Purified on a preparative silica gel plate, using 396 MeoN in SNSI. Methyl i-4-(2-(1-benzhydryl-2-I2-Kbenzylsulfonyl)amino|ethyl)-5-chloro-1H-indol-3-yl)ethyl|Iisulfonyl)benzoate is obtained - 50 (off-white substance) with output 94965.

Stage 10: Methyl

IR) 4-(2-(1-benzhydryl-2-I2-Kbenzylsulfonyl)amino|ethyl)-5-chloro-1H-indol-3-yl)ethyl|IisulfonylIbenzoate (Tech.),

THF (01M), Meon (ml/ml THF) and Mahon (n) (11 eq) are stirred overnight. Solvents are removed and the resulting residue is transferred to water. The solution is acidified with NCI and the precipitate obtained as a result is collected by filtration. They receive

Gee! 4-(2-(1-benzhydryl-2-I2-Kbenzylsulfonyl)amino|ethyl)-5-chloro-1H-indol-3-yl)ethyl|isulfonyl)ibenzoic acid (off-white substance) with a yield of 9295. MS high resolution computing. for (C z9NzvSIMoOv652-NI 725.15523, about 725.15437 was found.

Example 136: 60 0 4-(12-(/1-benzhydryl-5-chloro-2-(2-((2-chlorobenzyl)sulfonyl|aminoethyl)-1H-indol-3-yl|ethyl)isulfonyl)benzoic acid

Stage 1: To a mixture of methyl 3-I4-(12-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethyl)sulfonyl)phenyl|benzoate (Example 135, stage 8, Tekv), CH 2Si. (008M), water (uml/ml СНоСИ») and Ma»СбО53 (2.5 eq.) add 65 (2-chlorobenzyl)sulfonyl chloride (3.4 eq.). After 2 hours, more (2-chlorobenzyl)sulfonyl chloride (3.4 eq.) is added.

After an additional 1.5 hours, the organic layer is separated, washed with saturated salt solution and dried over sodium sulfate. Purified on a silica gel preparative plate using 396 Meons in SNESS.

Methyl 3-I4-(42-(/1-benzhydryl-5-chloro-2-(2-1(2-chlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Iethyl)isulfonyl)phenyl is obtained |benzoate (yellow-hot resin) with a yield of 40905.

Stage 2: Methyl 3-I(4-(2-(1-benzhydryl-5-chloro-2-(2-(2-chlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-z3-yl ethylsulfonyl)phenyl| benzoate (Teq), THF (0.1M), MeonH (mL/mL THF), and Masson (Tn) (11eq) were stirred together overnight. The solvents were removed and the resulting residue was taken up in water. The solution was acidified with 1N He and the resulting precipitate is collected by filtration. isulfonyl) benzoic acid (red-hot yellow solid) with a yield of 8095. High resolution MS calculated for

ISzenzasi»M2Ov5»2 NO 761.13081, found 761.13146.

Example 137: 4-(12-(/1-benzhydryl-5-chloro-2-(2-(1(2,6-difluorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-ilyethylusulfonyl)benzoin /5 and acid

Stage 1: To a mixture of methyl 3-I4-(12-(2-(2-aminoethyl-1)-benzhydryl-5-chloro-1H-indol-3-yl|ethyl)sulfonyl)phenyl|benzoate (example 135, stage 8, Eq.), CHCl" (0.08M), water (tIml/lml СНоБCl") and Ma»CO3 (2.5 eq.) add (2,6-difluorobenzyl)sulfonyl chloride (3.4 eq.). After 2 hours, the organic layer is separated, washed with a saturated solution of sodium chloride and dried over sodium sulfate. Purified on a silica gel preparative plate using 390 meon in СНоСИ». Methyl 4-(12-(/1-benzhydryl-5-chloro-2-(2-(1(2,6-difluorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|1ethylusulfonyl)benzoate is obtained ( solid off-white substance) with a yield of 87965.

Stage 2: Methyl 4-(12-(/1-benzhydryl-5-chloro-2-(2-H12,6-difluorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl)ethyl) sulfonyl) benzoate (Teq), THF (0.1 M), MeonH (Iml/Iml THF) and Maon(In) (11eq) are stirred together overnight. Solvents are removed and the resulting residue i) transferred to water. The solution is acidified with NH and the resulting precipitate is collected by filtration.

4-(12-(/1-benzhydryl-5-chloro-2-(2-(1(2,6-difluorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-ilyethylusulfonyl)benzoic acid is obtained (solid white-yellow substance) with a yield of 9695. High-resolution MS calculations for

ISzeNzzSIR»M2Ovo-NO 761.13638, found 761.13565. -

Example 138: "g 4-(12-(1-benzhydryl-5-chloro-2-(2-(1(2-fluorobenzyl)sulfonyl|aminoethyl)-1H-indol-3-yl|1-ethyl)sulfonyl)benzoic acid -

Stage 1: To the mixture of methyl i-3-I4-(12-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|hethyl)sulfonyl)phenyl|benzoate (example 135 , stage 8, Tekv), CH 2Si. (008M), water (ml/ml СНоСИ») and Ma»СбО53 (2.5 eq.) add (2-fluorobenzyl)sulfonyl chloride (3.4 eq.). After 2 hours, the organic layer is separated, washed with saturated salt solution and dried over sodium sulfate. Purified on a silica gel preparation plate, "

Using Zoo meon in SNoSI". Methyl sv) with 4-(12-(1-benzhydryl-5-chloro-2-(2-((2-fluorobenzyl)sulfonyl|aminoethyl)-1H-indol-3-ylethyl)isulfonyl)benzoate is obtained (solid mud -white substance) with a yield of 82965. i?Stage 2: Methyl 4-(12-(1-benzhydryl-5-chloro-2-(2-((2-fluorobenzyl)sulfonyl|aminoethyl)-1H-indole-3- ilyethyl)isulfonyl)benzoate equiv.), THF (0.1M), MeOH (1ml/1ml THF) and Mahon(Tn) (1Teq) are stirred together overnight.Solvents -I are removed and the resulting residue is taken up in water. The solution is acidified with 1N NOI and the resulting precipitate is collected by filtration.

Ш- 4-(12-(1-benzhydryl-5-chloro-2-(2-((2-fluorobenzyl)sulfonyl|aminoethyl)-1H-indol-3-yl|ethyl)sulfonyl)benzoic acid (solid mud -white matter) with an output of 9995. MS of high resolution calculated for

ISZENZASIEM2OVZ2-NO 743.1458, found 743.14511. - Example 139:

Ge 4-(2-71-benzhydryl-5-chloro-2-(2-(2-pyrrolidin-1-ylethanesulfonylamino)ethyl I|-1H-indole-3-iliethoxy)benzoic acid

Step 1: The compound was prepared from the intermediate of Example 87, Step 1 and pyrrolidine by the procedure of Example 87, Step 2 in a yield of 9295 without column purification.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, except that the pH is adjusted to 4-5, obtaining the acid indicated in the title with a yield (F, 9290. High-resolution MS calc. for |SzvNaoSIM3O55-NI 684.23044, found 684.23009. ka Example 140: 4-(12-(1-benzhydryl-5-chloro-2-(2-((3,4-dichlorobenzyl)sulfonyl|amino)ethyl )-1H-indol-3-ylethyl)usulfonyl)benzoic acid

Stage 1: To a mixture of methyl 3-I4-(12-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethyl)sulfonyl)phenyl|benzoate (Example 135, stage 8, Tekv), CH 2Si. (008M), water (ml/ml СНоСИ») and Ma»СбО53 (2.5 eq.) add (3,4-dichlorobenzyl)sulfonyl chloride (2.1 eq.). After 71 hours, the organic layer is separated, washed with 65% saturated salt solution and dried over sodium sulfate. Purified on a silica gel preparative plate using Zoo meon in СНоСИ». Methyl is obtained

4-(12-(1-Benzhydryl-5-chloro-2-(2-1(3,4-dichlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Hethyl)usulfonyl)benzoate (solid white substance) with an output of 87905.

Stage 2: Methyl 4-(12-(1-benzhydryl-5-chloro-2-(2-1(3,4-dichlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Hethyl)usulfonyl) benzoate (1eq), THF (01M), MeonH (1ml/ml THF) and Maon(Tn) (11eq) are stirred together overnight. Solvents are removed and the resulting residue is transferred to water. The solution is acidified with 1N NOI and the resulting precipitate is collected by filtration. Obtain 4-(12-(1-benzhydryl-5-chloro-2-(2-((3,4-dichlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-ilyethyl)usulfonyl)benzoin 7/0 U acid (a solid light-yellow substance) with a yield of 9395. High-resolution MS calcd. for

ISzvNazzSiIzM2Ov5»o-NO 793.07728, found 793.07629.

Example 141: 4-(12-(/1-benzhydryl-5-chloro-2-(2-((2,6-dimethylbenzyl)sulfonyl|amino)ethyl)-1H-indol-3-ylylethyl)isulfonyl)benzoic acid

Stage 1: To a mixture of methyl 3-I4-(12-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethyl)sulfonyl)phenyl|benzoate (Example 135, stage 8, Tekv), CH 2Si. (008M), water (iml/lml СНоСИ») and Ma»СбО53 (2.5 eq.) add (2,6-dimethylbenzyl)sulfonyl chloride (3.Eq., example 52, stage 1). After 2 hours, the organic layer is separated, washed with saturated salt solution and dried over sodium sulfate. Purified on a silica gel preparation plate using 395 MeonN in СНоСИ». Methyl 4-(12-(/1-benzhydryl-5-chloro-2-(2-((2,6-dimethylbenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethyl)sulfonyl)benzoate is obtained (solid light brown substance) with a yield of 1905.

Stage 2: Methyl 4-(12-(1-benzhydryl-5-chloro-2-(2-((2,6-dimethylbenzyl)sulfonyl|amino)ethyl)-1H-indole-3-ylylethylsulfonyl)benzoate (Eq. ), THF (01M), MeOonN (Iml/Iml THF) and Mmaon sc (In) (1Teq.) are stirred together overnight. The solvents are removed and the resulting residue is taken up in water. The solution is acidified with NH and the precipitate is collected by filtration, which fell out as a result. i)

4-(12-(/1-benzhydryl-5-chloro-2-(2-1(2,6-dimethylbenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethyl)sulfonyl)benzoin is obtained acid (solid white substance) with a yield of 9995. High resolution MS calcd. for |C 54NzoSi! SIM»Ovb5» NO from 753.18653, found 753.18597.

Method.) - "cha i - shi s z -I -I sh" - 50

Co.)

F) name) 60 b5 a SHY liz 70 ot Mn sho A kl KK diku u tiviv NYA PO pak z Pact m shi Uya

LYNE tshe geo kit dyut m ZNYI y v.o viya y tu zhit tu no KU vvyaz M-ge v a NK i yin nya syn nk yn nya . Method .-) offers an alternative scheme of reactions for a subset of the compounds contained in this document.

Accordingly, the substituted aniline is halogenated using ICI, I» or BiI2, and then the amine is protected in

In the form of a carbamate, using, for example, triethylamine and chloroformate. This aryl halide is combined with

Ge alkyne containing the appropriate functional groups using Pa and copper catalysts in the presence of a base such as triethylamine. This resulting product can be subjected to cyclization using

Ra catalyst in the presence of allyl chloride and a substituted oxirane. The indole nitrogen atom can then be alkylated by treatment with a strong base, such as sodium bis(trimethylsilyl)amide, n-Wily, sodium hydride, or potassium hydride in a solvent such as DMF, DMSO, or THF, followed by reaction with the appropriate halide. Allylindole (F) can then be treated with 9-BVM and then with a palladium catalyst, followed by the addition of an aryl or vinyl iodide to carry out the Suzuki coupling reaction. The resulting intermediate can be deprotected using hydrazine or an alkylamine to yield the primary amine. This amine can then be treated with the necessary sulfonyl chloride under biphasic conditions, an aqueous sodium bicarbonate/dichloromethane mixture, or in an organic solvent with the addition of a base that is a blocked organic amine. 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, it can be cleaved by treatment with sodium thiomethoxide in a solvent such as THF or DMF at elevated temperature (5020-1002). 65 Method K pera demon yazhon v nn i v a i o i I I v V OO M a ns NN zer re re kozh i, hissing mu Y as" pt s

Closing the field

And p «t on. ram M. iv - . . . . and Method K offers an alternative way to prepare the compounds of the present invention. Accordingly, the substituted aniline is halogenated using ICI, IO, or HO, and then the amine is protected as a carbamate or amide,

Using, for example, trifluoroacetic anhydride, triethylamine and dimethylaminopyridine. This intermediate -I compound is then reacted with an alkyne containing the appropriate functional groups using Ra and copper catalysts in the presence of a base. The resulting arylalkyne is subjected to cyclization to indole by heating

Sh- with an amine such as piperidine. Standard reaction conditions of Mitsunobu, phosphine, azodicarboxylate and phthalamide are used to obtain the protected amine. Indole can be alkylated at the NW position (C position of the indole carbon atom 5o) with aldehydes or the corresponding acetals in the presence of a Lewis or Brønsted acid such as boron trifluoride stearate or trifluoroacetic acid. The indole nitrogen can then be alkylated by treatment

Ge with a strong base such as sodium bis(trimethylsilyl)amide, n-Hylium, sodium hydride, or potassium hydride in a solvent such as DMF, DMSO, or THF, followed by reaction with the appropriate halide. The resulting intermediate can be deprotected using hydrazine or an alkylamine, leading to the primary amine. This amine can then be treated with the necessary sulfonyl chloride under biphasic conditions, an aqueous sodium bicarbonate/dichloromethane mixture, or in an organic solvent with the addition of a base, which

F) self-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 an elevated temperature.

Alternatively, it can be cleaved by treatment with sodium thiomethoxide in a solvent such as THF or DMA at elevated temperature (5020-1002).

Method Y. b5

What led

VE a i mesh i nn НВ ше и: 70 ee 2. in ste o

GI method. offers another alternative way of preparing the compounds of the present invention. Correspondingly, halogen-substituted aniline in the 35th way, see methods U and K, and a symmetrical alkynol or an alkynol with one protecting group m, for example, protected TNR, interacts in the presence of a base, copper and palladium catalysts, followed by deprotection under acidic conditions, if a substrate with one protecting group is used, giving a symmetrical indolediol . Symmetry is removed from the diol by treatment with carbonyldiimidazole in an appropriate solvent, and then the primary alcohol is replaced under standard Mitsunobu reaction conditions, and phosphine, azodicarboxylate, and alcohol are used to obtain the desired ether. The carbamate can be opened by reacting with sodium azide to give the alkyl azide. The indole nitrogen can then be alkylated by treatment with a strong base such as sodium bis(trimethylsilyl)amide, n-Bi, sodium hydride, or potassium hydride in a solvent such as DMF, DMSO, or THF, followed by reaction with corresponding halide. Wet treatment with triphenylphosphine

THF gives the desired alkylamine. The amine can then be treated with the necessary sulfonyl chloride under biphasic conditions, an aqueous sodium bicarbonate/dichloromethane mixture, or in an organic solvent with added base, -1 which is 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 an elevated temperature. Alternatively, -and cleavage can be accomplished by treatment with sodium thiomethoxide in a solvent such as THF or DMSO at 1" elevated temperature (5020-1002).

Method M -i

Ko) ime) 60 b5 their same zhh y nt 5 E o o se schi "I

M i- " - s ;" -I -I t» -I 50 more) (F) ko bo b5 and ki v a, some more I bika eh, not U m sho i write SHY a KN i - bolts of themes ni no. p x : yKya is adjectival RY 7 - B y ! ! Method M offers a further strategy for the preparation of compounds according to the present invention. Accordingly, the substituted aniline is halogenated using ICI, I' or HO, and then the amine can be alkylated using

Sh- an organic base and a halide. The alkylamine obtained in this way is then reacted using palladium as a catalyst in the presence of a source of chloride and a base with or without phosphine and the required alkyne, yielding 5o indole. When 7 in the alkyne is MNBZO 4(СНо)п2ХКи, the synthesis is completed by hydrolysis at basic

Sh- conditions with sodium hydroxide in a mixture of water, methanol and THF at room temperature or at elevated temperature

Ge temperature.

Alternatively, cleavage can be accomplished by treatment with sodium thiomethoxide in a solvent such as THF or DMSO at elevated temperature (5020-1002).

When 2-MNY"

The resulting indole can then be treated with the necessary sulfonyl chloride under biphasic and F) conditions, an aqueous sodium bicarbonate/dichloromethane mixture, or in an organic solvent with the addition of a base, which is 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 an elevated temperature. Alternatively, cleavage can be accomplished by treatment with sodium thiomethoxide in a solvent such as THF or DMSO at elevated temperature (5020-1002).

When 4-OH

The resulting alcohol can be converted to a halide or mesylate, for example, using methanesulfonyl chloride and an organic base, which can then be replaced with sodium azide in DMF. Obtained 65 As a result, the alkyl azide can be restored under the action of triphenylphosphine and wet THF. The amine can be sulfonylated by sulfonyl chloride under the biphasic conditions of Schott and Baumann, a mixture of aqueous bicarbonate and dichloromethane, or under anhydrous conditions in the presence of dichloromethane and an organic base such as M,M-diisopropylethylamine.

The intermediate compound obtained as a result is hydrolyzed using the base, Mahon, Kon, GiOH, and a mixture of solvents including alcohol, water and tetrahydrofuran.

Method M with (8) is similar

Fashion BUD. we era eye Anya sla - m.

EN BA s, y s, what what she no) s p nyn she NN h Me koyamya Sha a SY Penn Mi zhen beta, j zhe - and i -0.720 volya і- «

Ko) and . : with.

Method M offers a further strategy for obtaining a subset of the compounds of the present invention. 2-formylindole with a functional group in the SSZ position (see method A) interacts under the conditions of the Wittig reaction or other conditions of organometallic reactions, leading to the formation of an alkenoate ester. This ester can be converted into an acid by treatment with Ra, and the resulting unsaturated acid is reduced by hydrogenation.

HF) Alkyl acid is activated by conversion to chloride anhydride under the action of oxalyl chloride, or to fluorine anhydride with the help of cyanofluoride, and then treated with an appropriate borohydride reducing agent, obtaining an alcohol. The alcohol is converted to bromide using triphenylphosphine and carbon tetrabromide, and then the anion is replaced in the sulfonamide obtained by treating the primary sulfonamide with a strong base such as Ma, n-Bx, etc., to give the desired secondary sulfonamide. The resulting intermediate compound, which is a complex ester, is hydrolyzed using the base, MasH, KOH, HION, and a mixture of solvents including alcohol, water, and tetrahydrofuran.

Example 142: 4-I(2-(1-benzhydryl-2-(3-Kbenzylsulfonyl)amino|propyl)-5-chloro-1H-indol-3-yl)ethoxy|benzoic acid

Stage 1: 5.0 g of methyl ether is dissolved in 250 ml of tetrahydrofuran at room temperature

4-(2-(1-benzhydryl-2-formyl-1H-indol-3-yl)ethoxy|benzoic acid, stage 4, example 1 (0.0092M, eq.) and 5.0 g of allyl(triphenylphosphoranylidene)acetate ( 0.0139M, 1.5eq.) The pale yellow solution was stirred for one hour. TLC showed a new spot at a CI of 0.5 in 1:1 hexanes/ethyl acetate and no parent indole.

The reaction mixture is poured into 500 ml of ethyl acetate, washed with water (2 x 125 ml) and saturated salt solution (2 x 125 ml). The organic layer is dried over magnesium sulfate and filtered. The filtrate is evaporated to a yellow oily substance, which is dissolved in 50 ml of a 1:1 mixture of hexanes/ethyl acetate and filtered through a layer of silica gel to remove the main substance. 5.23 g of 4-(2-(2-(2-allyloxycarbonylvinyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoic acid methyl ether are obtained in the form of a yellow oily substance (yield 9196 ).

Stage 2: 6.12 g of 4-12-(2-(2-allyloxycarbonylvinyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoic acid methyl ether (0.098M, Chekv) is added to 7b5ml of THF .) and 1.12 gtetrakis(triphenylphosphine)palladium (0) (0.001 M, 0.Eq.). To the reaction mixture dropwise for 20 min. add 8.60 ml of morpholine (0.098 M, Teq.).

After the addition is complete, the reaction mixture is stirred at room temperature for 4 hours.

The reaction mixture was poured into 250 ml of ethyl acetate, and the organic solution was extracted with Mahon's solution (2 x 75 ml). The aqueous layers are combined and acidified with HCl, the acidic solution is extracted with ethyl acetate (33x7bml). The organic layers are combined and washed with a saturated salt solution (1x5Oml), dried over magnesium sulfate, filtered and evaporated, obtaining methyl ether 4-22-P1-benzhydryl-2-(2-carboxyvinyl)-5-chloro-1H-indole-3- yl|ethoxy)benzoic acid in the form of a yellow oily substance (5.4Ω, yield 97905).

Stage C: 400 mg of 4-2-11-benzhydryl-2-(2-carboxyvinyl)-5-chloro-1H-indole-3-yl|ethoxy)benzoic acid methyl ether (0.0007M, Chekv.) is dissolved in 15 ml of methanol. . 8Omg of 595 platinum on activated carbon is added to this solution in the form of a suspension in 5 ml of methanol. The black suspension is placed in a hydrogen atmosphere using a balloon and stirred for 24 hours at room temperature. The hydrogen is pumped off, another 8Omg of 570 platinum on activated carbon in 5 ml of methanol is added, and the reaction mixture is again placed in a hydrogen atmosphere using a balloon and stirred for an additional i) 24 hours at room temperature. The progress of the reaction is monitored by NMR and at this point complete conversion is noted. The reaction mixture is filtered through celite and the filtrate is evaporated, obtaining 4-2-P1-benzhydryl-2-(2-carboxyethyl)-5-chloro-1H-indol-3-yl|)|ethoxy)benzoic acid methyl ester as a solid

Zr Yellow-green substance (320 ml, output 7990).

Stage 4: In 1.0 ml of anhydrous methylene chloride, dissolve 17000 mg of methyl ether - 4-2-11-benzhydryl-2-(2-carboxyethyl)-5-chloro-1H-indol-3-yl|ethoxy)benzoic acid (0.0002M , Chekw.). 33.5 mg of oxalyl chloride (0.0003 M, 1.5 equiv.) is added to the E solution and the reaction mixture is stirred for one hour at room temperature. Then the reaction mixture is evaporated to dryness and the residue is dissolved in 1.0 ml of anhydrous ethyl ether, to which 0.027 ml of TMEBA is added. To this solution, add 0.35 ml of a solution of zinc borohydride in ether, prepared by the Tei method described in the literature. Gay. My. 22, p. 4723, 1981). The reaction mixture is stirred for 15 minutes. at room temperature and extinguish 1.0 ml of water. The reaction mixture is diluted with 10 ml of ethyl ether and the aqueous layer is separated, the organic layer is dried over magnesium sulfate, filtered and evaporated to obtain a transparent oily substance. The oily substance was chromatographed using a mixture of ethyl acetate/hexanes (1:9) to give the methyl ether with 4-2-P1-benzhydryl-5-chloro-2-(3-hydroxypropyl)-1H-indol-3-yl. vtoxy)benzoic acid in the form of a white foam. (81mg, output 83960). and?" Stage 5: 104.0 mg of 4-2-11-benzhydryl-5-chloro-2-(3-hydroxypropyl)-1H-indole-3-yl methyl ether is dissolved in 2.00 ml of anhydrous methylene chloride. ethoxy)benzoic acid (0.0002M, 1.Eq.). 116.0 mg of triphenylphosphine bound on polystyrene (1.61 mmol/m, 0.0002 M, 1.Eq.) is added to this solution, followed by the addition of 125.0 mg of carbon tetrabromide (0.0004 M, 2.Eq.). The suspension is stirred for 2 hours at room temperature, after which the reaction mixture is filtered and the filtrate is evaporated to

Sh - a yellow-hot oily substance. The oily substance is purified by column chromatography using a mixture of ethyl acetate/hexane (2:98), obtaining 100 mg (8695) of 4-2-11-benzhydryl-2-(3-bromopropyl)-5-chloro-1H-indole-Z3 methyl ether -yl|Iethoxy)benzoic acid in the form of a yellow foam. - Stage 6: 33.3 mg of o-toluenesulfonamide (0.0002 M, 1.2 equiv) is dissolved in 0.5 ml of DMF and this mixture is added

Kz to a suspension of 8.Omg 60905 sodium hydride (0.0002M, 1.2 equiv.) in 0.bml DMF. The reaction mixture is stirred continuously

Store, then add 100 mg of 4-2-11-benzhydryl-2-(3-bromopropoxy)-5-chloro-1H-indol-3-yl|ethoxy)benzoic acid methyl ether (0.0002M, 1.0 equiv. ) in 00.bBml of DMF and the solution is stirred for an additional hour. The reaction mixture is quenched with water and diluted with 10 ml of ethyl acetate. The organic layer is washed with water (2xbml) and saturated salt solution (2xb5ml), dried over magnesium sulfate and evaporated to a yellow oily substance. The residue was purified by column chromatography (ethyl acetate/hexanes 5:95), obtaining 20 mg (1796) of 4-2-P1-benzhydryl-5-chloro-2-(3-phenylmethanesulfonylaminopropyl)-1H-indole-3-yl|) methyl ester. |eetoxy) of benzoic acid in the form of a transparent oily substance.

Step 7: 20.Omg of indole from example 6 (0.00002M, eq.) is hydrolyzed as in example 1, stage 8, obtaining the title compound (13.Omg, yield 88905) t/2(M-1)691.

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An appropriately substituted halogenamine reacts with the corresponding halide and a tertiary amine base to provide an M-alkylated substrate for the Shonigishire coupling reaction (with an alkynol in the presence of the appropriate base). This arylalkynol is subjected to cyclization to indole under the action of copper halide and heat. The free alcohol is protected with a silyl protecting group by reacting with silyl chloride in the presence of a base such as imidazole. This indole is then subjected to C3 acylation by reacting with a suitable cochlorine anhydride, and the resulting compound is reduced with strong reducing agents, preferably borane or a borane complex. The primary alcohol is then oxidized to the aldehyde with any oxidizing agent, including 60 oxalyl chloride/DMSO (Svern conditions) or TPAR/MMO. This aldehyde is subjected to reductive amination conditions involving a borohydride reductant and, in some cases, a proton-containing acid and a primary or secondary amine. Then, silyl ether is deprotected with a fluorine source, including C35E, TVABE, NE, etc.

This free alcohol is converted into a leaving group, a halide, using SVg; and phosphine, or into a sulfonate ester with methanesulfonyl chloride and a tertiary amine. Activated alcohol 65 is reacted with sodium azide in DMF or DMSO, obtaining the desired azide, which, in turn, is reduced under the conditions

Staudinger, phosphine and a TTF/H.O mixture, or by hydrogenation using hydrogen and a suitable catalyst. The amine can be sulfonylated under sulfonyl chloride under the biphasic conditions of Schott and Baumann, a mixture of aqueous bicarbonate and dichloromethane, or under anhydrous conditions in the presence of dichloromethane and an organic base such as M,M-diisopropylethylamine. The resulting intermediate compound is hydrolyzed using a base, maon, con, GioOH, and a mixture of solvents including alcohol, water, and tetrahydrofuran.

In examples 143-151 below, the synthesis was carried out using the method of M.

Example 143: 4-(42-(1-benzhydryl-2-12-Kbenzylsulfonyl)amino|ethyl)-5-chloro-1H-indol-3-yl)ethylamino)benzoic acid

Stage 1: To a solution of 4-chloro-2-iodaniline (16.5g, 65.1mmol) in DMF (250ml) at room temperature 70 add o-bromodiphenylmethane (21.5g, 84.bmmol) and isor ME (23ml, 13Ommol ) and the reaction mixture is heated at 4592; overnight. After removal under reduced pressure of volatile components, the residue is dissolved in E(OAc, washed with water (3), saturated salt solution and dried over Ma5O"). Purification by chromatography on a column with

BIO" (hexanes - a mixture of 596 E (OAc/hexanes) gives the desired benzhydryl-(4-chloro-2-iodophenyl)amine (26.1 g, yield 97905) as a yellowish solid.

Stage 2: A mixture of benzhydryl-(4-chloro-2-iodophenyl)amine (26.1g, 62.2mmol), Rasi (PP) (1.90g, 2.67mmol),

Si! (1.2g, b.2mmol), Z-butyn-1-ol and EBM (120ml) are stirred at 4592 for 20 hours. The reaction mixture was filtered through Celite and washed with EtOAc. The filtrate is concentrated, redissolved in E(Ac, washed with water (35), saturated salt solution and dried over Mazo,. Crude 4-(2-(benzhydrylamino)-5-chlorophenyl|but-3-yn-1-ol (25 ,5g) are directly used at the next stage without additional purification.

Step 3: A solution of crude 4-(2-(benzhydrylamino)-5-chlorophenyl|but-3-yn-1-ol (25.5 g) and Si! (2.7 g, 14.1 mmol) in DMF (200 mL) is heated at 1259 for 24 hours. The reaction mixture is filtered through celite and washed with E(Ac. The filtrate is concentrated, redissolved in E(Ac, washed with water (3x), saturated salt solution and dried over Ma95O,. Chromatography on a column with silica gel (30956 E (Ac/hexanes) gives the desired CM 2-(1-benzhydryl-5-chloro-1H-indol-2-yl)ethanol as a yellow solid (14.5 g, yield 7395 over two stages).

Stage 4: To a solution of 2-(1-benzhydryl-5-chloro-1H-indol-2-yl)ethanol (15.3g, 42.3mmol) in CH 5Si" (190ml) at 02C, add imidazole (3.72g, 55.0 mmol) and TVORBZSI (13.2 ml, 50.6 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 Mo5O. The crude silyl ether is used directly in the next stage without additional purification. what-

Stage 5: Add oxalyl chloride (4.84 ml, 55.5 mmol) dropwise to a solution of crude silyl ether in EO (200 ml) at 09C. The reaction mixture is allowed to warm to room temperature and stirring is continued for 4 hours, after which Ei zM (Z0ml) and MeonN (1Oml) are added. The mixture is washed with water, saturated salt solution and dried over Ma5O). Crude ketoester is directly used in the next stage. -

Stage 6: To the ketoether in THF (300ml) at room temperature, add VN z.Me»5 (100M, Zbml) dropwise and the reaction mixture is refluxed overnight. The mixture is cooled to 0 2С, after which Mahon (3095, 150 ml) is added and stirring is continued for ЗОхв. THF is removed under reduced pressure "and the reaction mixture is extracted with EtOAc, washed with water, saturated salt solution and dried over Mao". -o 70 Purification by column chromatography (from 15 to 2095 E(Ac/hexanes) gives the desired product in the form of a white solid (15.9 g, 24.7 mmol, 5895 in three stages). :z» Stage 7: To oxalyl chloride solution (0.372ml, 4.27mmol) in CH-SiO (1Oml) at -7892C is added dropwise

DMSO (0.661 ml, 9.3 mmol). The reaction mixture is stirred at the same temperature for 5 minutes, after which a solution of 2-11-benzhydryl-2-(2-(tert-butyldiphenylsilanyloxy)ethyl|-5-chloro-1H-indole-3-ylethanol (2.50 g , -1 3.8 vmmol) in СНоСИ" (vml). After stirring for an additional 40 min. ZoRGOMEI (3.38ml, 19.4mmol) was added, the reaction mixture was quenched with cold water (bml) and extracted with CHCl". The organic layer was dried over Mo50O , and evaporate. Their crude 11-benzhydryl-2-(2-(tert-butyldiphenylsilanyloxy)ethyl|-5-chloro-1H-indol-3-ilyacetaldehyde directly 50r Used in the next stage. and Stage 8: To a solution of crude aldehyde (3.88 mmol) in 1,2-dichloroethane (30 ml) at 09C add methyl

He 4-aminobenzoate (645mg, 4.27mmol), acetic acid (1.3ml) and Mavn(OAc)". The reaction mixture is allowed to warm to room temperature overnight and quenched with cold Manso with. Treatment by extraction gives the desired 4-(2-71-benzhydryl-2-(2-(tert-butyldiphenylsilanyloxy)ethyl|-5-chloro-1H-indol-3-yl)ethylamino)benzoic acid methyl ester, which is used directly in the next stage without additional purification.

F) Stage 9: To the methyl ester of 4-(2-711-benzhydryl-2-(2-(tert-butyldiphenylsilanyloxy)ethyl|-5-chloro-1H-indol-3-yl)ethylamino)benzoic acid (3, 8 vmmol) in THF (25 ml) at 09C, a mixture of NOAc/1M TWABE (in THF) (2.33 ml:5.v ml) is added and the reaction mixture is stirred at room temperature for 18 hours. Workup by extraction, followed by trituration in a mixture of 590 EUtAs/hexane, gives the desired methyl ester of 4-2-11-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl|stylamino|lbenzoic acid , with a small admixture, in the form of a solid, muddy-white substance (9296, in three stages).

Step 10: To a solution of 4-2-(1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl)ethylamino|benzoic acid methyl ether (1.64g, C04mmol) in

EBM (0.63 bml, 4.5 bmmol) and Massey (0.282 ml, 3.b4mmol) are added to НоСИ" at 02С. After stirring at the same temperature for ZBhv. the reaction mixture is quenched with cold water. Extraction treatment gives the crude mesylate as a solid off-white substance (1.7Og, 90905).

Step 11: A solution of crude mesylate (1.70g, 2.75mmol) and Mam z (89mg, 13.dmmol) in DMF (14ml) was stirred at 802C for 6 hours. The reaction mixture is diluted with E(OAc) and treated with water, followed by flash column chromatography, obtaining the desired methyl ester 4-2-(2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indole-3- iliethylamino|benzoic acid (813 mg, yield 52965).

Step 12: To 4-(2-(2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-ylylethylamino|benzoic acid) methyl ester (400mg, 0.709mmol) in THF 7/0 ( 1 ml) at 09C, add pHZR (22 µg, 0.851 mmol) in portions. The reaction mixture is stirred at room temperature for 11 hours and at 3593 for 4 hours, after which water (5 µM) is added and stirring is continued overnight. The reaction mixture is diluted with E(Ac , dried over Mo50O, and purified by flash column chromatography (from EtOAc to a mixture of 2096 Meon/EtOAc with 195 EBM), obtaining the desired methyl ether 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro- 1H-indol-3-yl|ethylamino|benzoic acid (201 mg, 5395) in the form of 75 solids.

Step 13: The intermediate from step 8 was treated with o-toluenesulfonyl chloride according to the procedure of Example 87, step 2, to give the desired product in 7295 yield.

Step 14: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with step 8 of example 1 to give the title acid in a yield of 8795. High resolution MS calcd. for |SzeNzeSIMzo,5 ANI 678.21879, found 678.2178.

Example 144: 4-(12-(/1-benzhydryl-5-chloro-2-(2-((2-chloro-6-methylphenyl)sulfonyl|amino)ethyl)-1H-indol-3-ylethyl)iamino) benzoic acid

Step 1: The intermediate of Example 143, Step 12 was treated with 2-chloro-6-methylbenzenesulfonyl chloride He by the procedure described in Example 87, Step 2 to give the desired product in a yield of 85905. (5)

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9695. MS high-resolution calculations. for

ISzenZ5SIMAZO, ANI 712.17981, found 712.17895.

Example 145: c 4-42-(/1-benzhydryl-5-chloro-2-(2-(:(2-methoxyphenyl)sulfonyl|amino)ethyl)-1H-indol-3-ylethyl)amino)benzoic acid

Step 1: The intermediate of Example 143, Step 12 is treated with 2-methoxybenzenesulfonyl chloride according to the procedure described in Example 87, Step 2 to give the desired product in a yield of 85905. M

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9295. MS high-resolution calculations. for -

ISzenzeSIMzO5 ANI 694.2137, found 694.21311.

Example 146: 4-(12-(/1-benzhydryl-5-chloro-2-(2-((2-chlorophenyl)sulfonyl|aminoethyl)-1H-indol-3-yl|ethylamino)benzoic acid "

Step 1: The intermediate of Example 143, step 12 is treated with 2-chlorobenzenesulfonyl chloride according to the procedure described in Example 87, step 2, to give the desired product in yield 2195. - c Step 2: The intermediate, which is an ester, is hydrolyzed according to stage 8 h of example 1, obtaining the acid indicated in the title with a yield of 9495. MS high-resolution calculations. for ,» ISzvNazSi»M30.5 NO 698.16416, found 698.16365.

Example 147:

A-(2-(1-benzhydryl-2--2-Kbenzylsulfonyl)amino|ethyl)-5-chloro-1H-indol-3-yl)ethylImethyl)amino|benzoic acid - and Stage 1: Crude -1 11- benzhydryl-2-(2-(tert-butyldiphenylsilanyloxy)ethyl|-5-chloro-1H-indol-3-ilyacetaldehyde from step 7 of example 143 is treated with 4-methylaminobenzoic acid methyl ester by the procedure described in example 143, step 8, obtaining the desired methyl ester -1 50 А-(2-11-benzhydryl-2-(2-(tert-butyldiphenylsilanyloxy)ethyl|-5-chloro-1H-indol-3-yl)ethyl)methylamino|benzoic acid with a yield of 73905 .what) Step 2: The title compound is prepared by the procedure described in Example 143, Step 9.

Crude methyl ester of 4-(12-(/1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-ilyuethyl|Imethylamino|Ibenzoic acid) is directly used in the next stage without additional purification. o Stage 3 -6: Methyl ether of 4-(12-(2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|Hyethyl|methylamino|benzoic acid) is obtained by the procedure described in example 143 , stages 10-12 with an output of 6195 (by stage 3).

Stage t. A solution of the methyl ether of 4-(42-(2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|Liethyl|methylamino|benzoic acid) (410 mg,

О.709 mmol) and 1095 Ra/С (155 mg) in a mixture of MeOH/СНОСИ" (Uml: 1 ml) are stirred in an atmosphere of NO (Tatm.) for 2 hours and 15 minutes. The reaction mixture is filtered through celite and washed with MeOH and СНоСиИ. Flash column chromatography of the residue (from CHCl to 895 Meon/CnNoCl) gives the desired methyl ester 4-((2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indole-3- ylphiethyl|methylamino|benzoic acid with a yield of 7890 65 (305 mg).

Step 8: The intermediate from step 7 was treated with a-toluenesulfonyl chloride according to the procedure described in Example 87, step 2, to give the desired product in a yield of 83905.

Stage 9: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9195. MS high-resolution calculations. for

ISzenzvSIMAZO,ZyNI 692.23444, found 692.23374.

Example 148: 4-C2-(/1-benzhydryl-5-chloro-2-(2-1(3,4-dichlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-ylylacetylmethyl)amino|benz oleic acid

Step 1: The intermediate of Example 147, Step 7 was treated with 3,4-dichlorophenylmethanesulfonyl chloride 7/0 by the procedure described in Example 87, Step 2 to give the desired product in 87905 yield.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 6895. MS high-resolution calculations. for

ISloNzeSizM3045 ANI 760.15649, found 760.1573.

Example 149: 4-C2-(/1-benzhydryl-5-chloro-2-(2-C(2-chloro-6-methylphenyl)sulfonyl|amino)ethyl)-1H-indol-3-ylphenylmethyl)amino|benzoin acid

Step 1: The intermediate of Example 147, Step 7 was treated with 2-chloro-6-methylbenzenesulfonyl chloride according to the procedure described in Example 87, Step 2 to give the desired product in 96905 yield.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 8895. MS high-resolution calculations. for 20. ISaoNz7SioM3OZ'NI 726.19546, found 726.19461.

Example 150: 4-C2-(1-benzhydryl-5-chloro-2-(2-C(2-chlorophenyl)sulfonyl|amino)ethyl)-1H-indol-3-ylethylmethyl)amino|Cbenzoic acid

Step 1: The intermediate of Example 147, Step 7 was treated with 2-chlorobenzenesulfonyl chloride, following the procedure described in Example 87, Step 2, to give the desired product in 9695 yield.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 i) of example 1, obtaining the acid indicated in the title with a yield of 8495. MS high-resolution calculations. for

ISzeNz5SI»M30.5'ANI 712.17981, found 712.17966.

Example 151: czo 4-(2-(1-benzhydryl-5-chloro-2-(2-H(2-methoxyphenyl)sulfonyl|aminoethyl)-1H-indol-3-ylylmethyl)amino|benzoic acid -

Step 1: The intermediate of Example 147, Step 7 was treated with 2-methoxybenzenesulfonyl chloride according to the procedure described in Example 87, Step 2 to give the desired product in 9595 yield.

Stage 2: The intermediate compound, which is an ester, is hydrolyzed according to stage 8-

From example 1, obtaining the acid indicated in the title with a yield of 7395. High-resolution MS calcd. for M

ISLONZVSIMZOBA ANI 708.22935, found 708.2286.

Example 152: 4-(3-P1-benzhydryl-5-chloro-2-(2-1(2,4-dichlorophenyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|propyl)ubenzoic acid

Stage 1: 2,4- dichlorobenzenesulfonyl chloride by the procedure of example 1, stage 7, obtaining the product -ptv) with a yield of 9595. . Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8a of example 1, obtaining the acid indicated in the title with a yield of 7795. MS high-resolution calculations. for

SzeNzzSIM2O,5 730.1227, found (ERY) 731.1299,

Example 153: -I 4-(3-P1-benzhydryl-5-chloro-2-(2-1((2,6-dichlorophenyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|propyl)ubenzoin acid

Stage 1: To methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6,

Ш- example 42) add 2,6-dichlorobenzenesulfonyl chloride by the procedure of example 1, stage 7, obtaining a product with a yield of 9395.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 7195. MS high-resolution calculations. for

From SzeNzazSiIzMoO,Z 730.1227, found (ERI) 731.13005.

Example 154: 4-(3-P1-benzhydryl-5-chloro-2-(2-1(2,4,6-trichlorophenyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Ipropyl)benzoin Acid

Stage 1: To methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6,

F) example 42) add 2,4,6-trichlorobenzenesulfonyl chloride by the procedure of example 1, stage 7, obtaining a product with a yield of 76905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 84906. High-resolution MS calcd. for

SzeNz" SI. MO, 764.0837, found (ERI) 765.08981.

Example 155: 4-(3-P1-benzhydryl-5-chloro-2-(2-S((2-cyanophenyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Ipropyl)benzoic acid

Stage 1: 2-cyanobenzenesulfonyl chloride is added to methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6, 65 example 42) by the procedure of Example 1, step 7, giving product with a yield of 87905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1 and purified by preparative HPLC to give the title acid in a yield of 895. High-resolution MS calcd. for С4оНазаСИМаО,5 687.1959, found (ERI) 688.2019.

Example 156: 4-(3-2-(2-442-(alinomethyl)phenyl|sulfonyl)amino)ethyl|-1-benzhydryl-5-chloro-1H-indol-3-yl)ipropyl)benzoic acid

Stage 1: Methyl 4-(3-P1-benzhydryl-5-chloro-2-(2-S(2-cyanophenyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Ipropyl)benzoate (example 7/ 0. 154, stage 1, 0.43 g, 0.6 mmol) is dissolved in THF (4 ml) and MeonH (12 ml). Cobalt (II) chloride (0.16 g, 1.2 mmol) and Mavn (0.23 g, 6 mmol) are added. After 2 hours, the mixture is filtered, concentrated and subjected to chromatography on silica gel (MeOH-CHNOCl), obtaining the amino ester with a yield of 13905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 5995. MS high-resolution calculations. for 75... SzenzeSIMzOB5Z 693,2064, found (ERY) 69421261.

Example 157: 4-I3-(1-benzhydryl-2-22-(1,1"-biphenyl-2-ylsulfonyl)amino|ethyl)-5-chloro-1H-indol-3-yl)/propyl|bDenoic acid

Stage 1: 2-Bromodiphenyl (0.55ml, 3.2mmol) is dissolved in THF (1Oml) and EB2O (1Oml) and cooled to -782C, at the same time rapidly adding n-Via and (1.3ml, 2 .5M solution in hexane, C3.2mmol). After 40 min. the mixture is added using a cannula to a solution of BO" (10 ml) in EBO (20 ml) cooled to -782C. The mixture is heated to room temperature overnight, concentrated and triturated in ESH2O. The resulting solid white substance is suspended in hexane (40 ml) and cooled to 02. Sulfuryl chloride is added (with 4 ml of a 1.0 M solution in

СНоСИ», 34 mmol) and the mixture is stirred at room temperature for 5 hours. Then it is concentrated, obtaining 2-diphenylsulfonyl chloride with a yield of 67905. s

Stage 2: 2-biphenylsulfonyl chloride is added to methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6, example 42) by the procedure of Example 1, step 7, giving product with a yield of 83905.

Stage 3: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9895. MS high-resolution calculations. for Ge

Cl5BNzoSiiM2O,5 738.2319, found (ERYHk) 739.23825.

Example 158: - 4-(3-P1-benzhydryl-2-(2-(2-bromophenyl)sulfonyl|aminoethyl)-5-chloro-1H-indol-3-yl|propyl)benzoic acid chI

Stage 1: To methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6, example 42) is added 2-bromobenzenesulfonyl chloride by the procedure of the example 1, step 7, giving the product with - yield 76905. -

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9595. MS high-resolution calculations. for

ISzenzaVgo!M20.5ANI 740.1111, found (ERI) 741.11696. "

Example 159: 40... А-2-(1-benzhydryl-5-chloro-2-(2-(I(2,4-dichlorophenyl)sulfonyl|amino)ethyl)-1H-indol-3-yl)ethoxy | benzoic acid - c Stage 1: This compound is obtained from methyl a 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and "» 2,4-dichlorobenzenesulfonyl chloride by the procedure of example 1, stage 7 with a yield of 83905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 8095. MS high-resolution calculations. for -i SzvNiyaSizMoOv 732.1019, found (ERI) 733.10824. -1 Example 160: 4-2-11-benzhydryl-5-chloro-2-(2-S(2,6-dichlorophenyl)sulfonyl|amino)ethyl)-1H-indole-3-ylethoxy|benzoic acid

ChK» Stage 1: This compound is obtained from methyl -1 50 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indole-3-ilyethoxy)benzoate (stage b, example 1) and 2,6-dichlorobenzenesulfonyl chloride by the procedure of Example 1, Step 7 in a yield of 77905. that) Step 2: The ester intermediate is hydrolyzed according to Step 8 of Example 1 to give the title acid in a yield of 8295. MS of high distinction of calculations for

SzvNiyaSizMoOv 732.1019, found (ERI) 733.10836. 5B Example 161: 4-2-11-benzhydryl-5-chloro-2-(2-ShC(2,4,6-trichlorophenyl)sulfonyl|amino)ethyl)-1H-indol-3-yl)ethoxy|benzoic acid acid ime) Stage 1: This compound is obtained from Kk) methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and 2,4,6-trichlorobenzenesulfonyl chloride by the procedure of example 1, stage 7 with a yield of 9095.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 8795. MS high-resolution calculations. for

SzvNzosSiI.MoO55 766.0630, found (ERI) 767.07063.

Example 162: 65 4-2-(/1-benzhydryl-5-chloro-2-(2-((2-cyanophenyl)sulfonyl|amino)zetyl)-1H-indol-3-yl)ethoxy|benzoic acid

Stage 1: This compound is obtained from methyl

4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and 2-cyanobenzenesulfonyl chloride by the procedure of example 1, stage 7 with an output of 82965.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1. It is purified by preparative HPLC, obtaining the acid indicated in the title with a yield of 1795. High resolution MS calcd. for SzoNazoSIMzOvB5 689.1751; found (ERI) 690.18082.

Example 163: 4-(2-2-(2-442-(aminomethyl)phenyl|sulfonyl)amino)ethyl/|-1-benzhydryl-5-chloro-1H-indole-3-ilyethoxy)benzoic acid 70 Stage 1: Methyl 4-2-11-benzhydryl-5-chloro-2-(2-N(2-cyanophenyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoate (Example 161, stage 1, 0 ,31g, O0.44mmol) is dissolved in THF (4ml) and Meon (12ml). Add cobalt chloride (II) (0.11g,

O.v8mmol) and Mavn (0.17g, 4.4mmol). After 2 hours, the mixture is filtered, concentrated and chromatographed on silica gel (Meon-CHNOCl), obtaining the amino ester with a yield of 17905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 3995. MS high-resolution calculations. for

SzenzeSIMAO55 693.2064, found (ERIFk) 694.21261.

Example 164: 4-(2-(1-benzhydryl-2-22-(1,1"-biphenyl-2-ylsulfonyl)amino|ethyl)-5-chloro-1H-indol-3-yl)ethoxy|Ibenzoic acid

Stage 1: The sulfonamide is obtained from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and 2- of diphenylsulfonyl chloride (Stage 1, Example 156) by the procedure of Example 1, Stage 7 to yield 93905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9495. MS high-resolution calculations. for the village

Sa«NztSIM2O5Z 740.2112, found (ERY) 741.21709.

Example 165: (8) 4-2-11-benzhydryl-2-(2-(2-bromophenyl)sulfonyl|aminoethyl)-5-chloro-1H-indol-3Z-yl)ethoxy|Ibenzoic acid

Stage 1: This compound is obtained from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and c with 2-bromobenzenesulfonyl chloride by the procedure of example 1, stage 7 with a yield of 9095.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 - example 1, obtaining the acid indicated in the title with a yield of 9195. MS high-resolution calculations. for "

SzvNz»VgSIMoOv5 742.0904, found (ERY) 743.09697.

Example 166: c. 4-(3-P1-benzhydryl-5-chloro-2-(2-S(5-chloro-2,4-difluorophenyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Ipropyl)ubenzoin acid

Stage 1: 5-chloro- 2,4-difluorobenzenesulfonyl chloride by the procedure of Example 1, step 7, to give the product in yield 6895.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 from c of example 1, obtaining the acid indicated in the title with a yield of 4495. MS high-resolution calculations. for

Y ISzenzoSioB2M20.5NI 733.15007, found 733.14978. and? Example 167: 4-(3-P1-benzhydryl-5-chloro-2-(2-S(2-methoxy-4-methylphenyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Ipropyl)ubenzoin

Acid -I Stage 1: 2 -methoxy-4-methylbenzenesulfonyl chloride by the procedure of example 1, stage 1, obtaining the product with a yield of 86905. their Stage 2: The intermediate compound, which is an ester, is hydrolyzed in accordance with stage 8 5r of example 1, obtaining the acid indicated in the title with a yield 3975. MS of high resolution calculation for sh- ISliNzeSIM2OBANI 707.2341, found 707.23407.

Ge Example 168: 4-(3-P1-benzhydryl-5-chloro-2-(2-X(4-chloro-2,5-difluorophenyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Ipropyl )ubenzoic acid

Stage 1: 4-chloro- 2,5-difluorobenzenesulfonyl chloride by the procedure of Example 1, Step 7, to give (F) product in a yield of 79905. ka Step 2: The ester intermediate is hydrolyzed according to Step 8 of Example 1 to give the title acid in a yield of 6395. MS of high resolution calculation for ISZENZOSIOR2M20UZNI 733.15007, found 733.14882.

Example 169: 4-2-11-benzhydryl-5-chloro-2-(2-CH(5-chloro-2,4-difluorophenyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy) benzoin acid

Stage 1: This compound is obtained from methyl 65 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and of 5-chloro-2,4-difluorobenzenesulfonyl chloride by the procedure of Example 1, step 7, to give the product with the yield

Zv.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 3195. MS high-resolution calculations. for 5. ISzvNzoSioRoMoOBZ'N) 735.12933, found 735.12824.

Example 170: 4-2-11-benzhydryl-5-chloro-2-(2-CH(4-chloro-2,5-difluorophenyl)sulfonyl|amino)ethyl)-1H-indole-3-iliethoxy)benzoic acid

Stage 1: This compound is obtained from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and 70 of 4-chloro-2,5-difluorobenzenesulfonyl chloride by the procedure of example 1, stage 7 with a yield of 7990.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 6395. MS high-resolution calculations. for

ИЗвНзоСиоБ2М2О55 NO 735.12933, found 735.12913.

Example 171: 4-2-P1-benzhydryl-5-chloro-2-(2-S(2-methoxy-4-methylphenyl)sulfonyl|amino)ethyl)-1H-indol-3-ylethoxy)benzoic acid

Stage 1: This compound is obtained from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and 2 -methoxy-2-methylbenzenesulfonyl chloride by the procedure of example 1, stage 7.

Step 2: The crude intermediate, which is an ester, is hydrolyzed according to step 8 of example 1, obtaining 407 mg of the title acid in quantitative yield. MS of high resolution calculations. for |SloNaU SIMoOb5'ANI 709.21337, found 709.21194.

Example 172. Z-il|Ipropyl)b sc ob enzoic acid

Stage 1: To methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6, i) example 42) add 4-chloro -7-chlorosulfonyl-2,1,3-benzoxadiazole by the procedure of Example 1, step 7, to give the product in a yield of 43905.

Step 2: The ester intermediate is hydrolyzed according to step 8c of Example 1 to give the title acid in a yield of 2670 after HPLC separation. MS of high resolution calculations. for |SzaNz»Si2MaO55ANI 739.15433, found 739.1537. -

Example 173: "g 4-(3-P1-benzhydryl-5-chloro-2-(2-1(7-methoxy-2,1,3-benzoxadiazol-4-yl)usulfonyl|amino)ethyl)-1H- Indole-Z3-yl)ipropyl)benzoic acid

Stage 1: 4-chloro is added to methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6, example 42) -7-chlorosulfonyl-2,1,3-benzoxadiazole by the procedure of Example 1, step 7, to give the product in a yield of 43905.

Step 2: The ester intermediate is hydrolyzed according to step 8 of example 1 to give the title acid in a yield of 3695 after HPLC separation. MC of high "distinction of calculations. for |SloNzvSIMa.O6Z'ANI 735.2046, found 735.2029. in c Example 174: . 4-22-P1-benzhydryl-5-chloro-2-(2-1(7-chloro-2,1,3-benzoxadiazol-4-yl)usulfonyl|amino)ethyl)-1H-indol-3-yl| iethoxy) and benzoic acid

Stage 1: This compound is obtained from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and - And 4-chloro-7-chlorosulfonyl-2,1,3-benzoxadiazole by the procedure of example 1, stage 7 with a yield of 56905.

Step 2: The ester intermediate is hydrolyzed according to step 8 of Example 1 to give the title acid in a yield of 3095 after HPLC separation. MC of high resolution of calculations. for (Szv6NaoSi»M.Ov65'ANI 741.1343, found 741.1328.

Example 175:

Sh- 4-2-(1-benzhydryl-5-chloro-2-(2-1(7-methoxy-2,1,3-benzoxadiazol-4-yl)usulfonyl|amino)ethyl)-1H-indole-Z -il)etok

From sy|benzoic acid

Stage 1: This compound is obtained from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and 4 -chloro-7-chlorosulfonyl-2,1,3-benzoxadiazole by the procedure of example 1, stage 7 with a yield of 56905.

Step 2: The intermediate compound, which is an ester, is hydrolyzed in accordance with step 8 (F, Example 1) to give the title acid with a yield of 3695 after HPLC separation. High resolution MS calcd. for (SzoNazzSIM.O75 NO 737, 1838, found 737,1819.

Example 176: 4-3-1-benzhydryl-5-chloro-2-(2-(115-(2-methyl-1,3-thiazol-4-yl)thien-2-yl|Isulfonylamino)ethyl/| -1H-indole-3-ylpropyl)benzoic acid

Stage 1: 5-(2- methyl-1,3-thiazol-4-yl)thiophene-2-sulfonyl chloride by the procedure of Example 1, Step 7, to give the product in a yield of 9090. 65 Step 2: The intermediate, which is an ester, is hydrolyzed according to Step 8 of Example 1, obtaining the title acid with a yield of 10095. High resolution MS calcd. for

ISl1NzvSIMAO455 NO 766D6Z6, found 766.1629.

Example 177: 4-(2-711-benzhydryl-5-chloro-2-(2-(15-(2-methyl-1,3-thiazol-4-yl)thien-2-yl|isulfonylamino)ethyl|- 1H-indol-3-yl)ethoxy)benzoic acid

Stage 1: This compound is obtained from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and 5 -(2-methyl-1,3-thiazol-4-yl)thiophene-2-sulfonyl chloride by the procedure of example 1, stage 7 with a yield of 10095.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 7/0 of example 1, obtaining the acid indicated in the title with a yield of 9275. MS high-resolution calculations. for

ISlonzaSIMzO5Za-NI 767.1269, found 766.1259.

Example 178: 4-(2-(1-benzhydryl-5-chloro-2-12-K(thien-3-ylsulfonylamino|ethyl)-1H-indol-3-yl)ethoxy|benzoic acid

Stage 1: This compound is obtained from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and

C-thiophenesulfonyl chloride by the procedure of example 1, stage 7 with a yield of 91965.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9695. MS high-resolution calculations. for

ISzvNaziSIMoOvo NO 671.14357, found 671.1428.

Example 179: 4-2-11-benzhydryl-5-chloro-2-(2-1(6b-morpholin-4-ylpyridin-3-yl)usulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy )benzoic acid

Stage 1: This compound is obtained from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and of 8-Morpholino-3-pyridinesulfonyl chloride by the procedure of example 1, stage 7 with a yield of 91905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 i) of example 1, obtaining the acid indicated in the title with a yield of 9295. MS high-resolution calculations. for

ISliNzeSIMAO65 NO 751.23516, found 751.2345.

Example 180: c zo 4-I3-(1-benzhydryl-5-chloro-2-12-Thien-3-ylsulfonyl)amino|ethyl)-1H-indol-3-yl)ipropyl|Senzoic acid

Stage 1: To methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6, - example 42) add 3-thiophenesulfonyl chloride by the procedure of example 1, stage 7, obtaining a product with a yield of 8790 g.

Stage 2: The intermediate compound, which is an ester, is hydrolyzed according to stage 8-

From example 1, obtaining the acid indicated in the title with a yield of 9995. MS high-resolution calculations. for M

ISa7NzzSIM2O)52 NO 669.16431, found 669.1629.

Example 181: 4-(3-P1-benzhydryl-5-chloro-2-(2-1(b-morpholin-4-ylpyridin-33-yl)usulfonyl|iamino)ethyl)-1H-indol-3-yl| Ipropyl)benzoic acid «

Stage 1: To methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6, from example 42) add b-morpholino -3-pyridinesulfonyl chloride by the procedure of example 1, stage 7, obtaining . product with an output of 79905. and? Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 8995. MS high-resolution calculations. for 45. ISdoNaSIMAOBZ'AN) 749.2559, found 749.255. -I Example 182: 4-(2-711-benzhydryl-2-(2-(benzo|1,2,5|oxadiazole-4-sulfonylamino)ethyl|-5-chloro-1H-indol-3-yl)ethoxy | benzoic acid their Stage 1: This compound is obtained from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b , example 1) and

Ш-benzofuran-4-sulfonyl chloride by the procedure of example 1, stage 7 with a yield of 88905.

Ge Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9495. MS high-resolution calculations. for

ISzvNaz1SIMAO65' NO 707.17256, found 707.1719.

Example 183: 4-(3-71-benzhydryl-2-(2-(benzo|1,2,5)oxadiazole-4-sulfonylamino)ethyl|-5-chloro-1H-indol-3-yl)propyl|IbSenzoin (F, acid) Stage 1: To methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6, example 42) is added benzofuran-4-sulfonyl chloride by the procedure of Example 1, step 7, to give the product with a yield of 69906.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9395. MS high-resolution calculations. for

ISzeNzzSIMAOV" NO 705,1933, found 705,1931.

Example 184: 65 4-(2-71-benzhydryl-2-(2-(2-benzyloxybenzenesulfonylamino)ethyl/|-5-chloro-1H-indol-3-yl)ethoxy|benzoic acid

Stage 1: This compound is obtained from methyl

4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and 2-benzyloxybenzenesulfonyl chloride by the procedure of example 1, stage 7 with an output of 8795.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9595. MS high-resolution calculations. for

ISl5NzeSIMOO65-NO 769.21446, found 769.2129.

Example 185: 4-(2-71-benzhydryl-5-chloro-2-(2-(2-isopropoxybenzenesulfonylamino)ethyl/|-1H-indol-3-yl)ethoxy|benzoic acid

Stage 1: This compound is obtained from methyl 70 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and of 2-isopropoxybenzenesulfonyl chloride by the procedure of example 1, stage 7 with a yield of 88905.

Step 2: The ester intermediate is hydrolyzed according to step 8 of example 1 to give the title acid in a yield of 7490 after trituration in diethyl ether. MS of high resolution calculations. for |C44NzoSIM2O65'ANI 723.22902, found 723.2284.

Example 186: 4-(3-1-benzhydryl-5-chloro-2-(2-(2-isopropoxybenzenesulfonylamino)ethyl/|-1H-indol-3-yl)ipropyl|Senzoic acid

Stage 1: To methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6, example 42) is added 2-isopropoxybenzenesulfonyl chloride by the procedure of the example 1, step 7, yielding product 71905.

Step 2: The ester intermediate is hydrolyzed according to step 8 of example 1 to give the title acid in a yield of 8290 after HPLC purification. MS of high resolution calculations. for |C42NASIM2OBZANI 721.24975, found 721.2490.

Example 187: 4-(3-71-benzhydryl-2-(2-(2-benzyloxybenzenesulfonylamino)ethyl|-5-chloro-1H-indol-3-yl)ipropyl|Senzoic acid

Stage 1: To methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6, example 42) is added 2-benzyloxybenzenesulfonyl chloride by the procedure of the example 1, step 7, yielding i) product with a yield of 57905.

Step 2: The ester intermediate is hydrolyzed according to step 8 of example 1 to give the title acid in a yield of 9790 after HPLC purification. MS of high s with the distinction of calculations. for |Sl6Na(SIMoO5Z'ANI 769.2505, found 769.2494.

Example 188: 4-(3-11-benzhydryl-2-(2-(2-hydroxybenzenesulfonyl-amino)ethyl/|-1H-indol-3-yl)ipropyl|Senzoic acid "E

Stage 1: The benzyl group from stage 1 of example 186 is removed by hydrogenolysis. The crude substance is purified on a column with silica gel using CHCl - 596 EUAs/CHNOCl" with the formation of a mixture, which is further purified -

HPLC, yielding methyl ester of y-4-(3-11-benzhydryl-2-(2-(2-hydroxybenzenesulfonylamino)ethyl|-1H-indol-3-yl)upropyl|bPhenzoic acid (795) and methyl ester of 4-( 3-71-benzhydryl-5-chloro-2-(2-(2-hydroxybenzenesulfonylamino)ethyl/|-1H-indol-3-yl)ipropyl|bSenzoic acid (1890).

Stage 2: An intermediate compound, which is a methyl ester of c 4-(3-71-benzhydryl-2-(2-(2-hydroxybenzenesulfonylamino)ethyl/|-1H-indol-3-yl)propyl|benzoic acid, . hydrolyze in accordance with step 8 of example 1, obtaining the acid indicated in the title with a yield of 81905. and high resolution MS calculated for (SzoNzeM2O55'ANI 645.2418, found 645.2423.

Example 189: 4-(3-71-benzhydryl-5-chloro-2-(2-(2-hydroxybenzenesulfonyl-amino)ethyl|-1H-indol-3-yl)propyl|bSenzoic acid -I Stage 1: Intermediate compound , which is the methyl ester of 4-(3-71-benzhydryl-5-chloro-2-(2-(2-hydroxybenzenesulfonylamino)ethyl|-1H-indol-3-yl)propyl|Ibenzoic acid,

Sh- from stage 1 of example 187 is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid specified in the title with a yield of 8695. MS of high resolution calculations. for |(СзоНз5СИМ2О55 NO 679.2058, found 679.2038.

Example 190:

Ш- 4-(2-71-benzhydryl-5-chloro-2-(2-(2-chlorobenzenesulfonyl-amino)ethyl-1H-indol-3-yl)ethoxy|-2-fluorobenzoin

From acid

Stage 1: Diisopropylazodicarboxylate (0.55 ml, 2.7 mmol, 2.0 equiv) was slowly added to a solution of RI zR (698 mg, 2./mmol, 2.Oeq) in THF (1Oml) at 02C under Mo atmosphere. The mixture is stirred for 5B 15 min. A solution of 2-11-benzhydryl-2-(2-(tert-butyldiphenylsilanyloxy)ethyl|-5-chloro-1H-indol-3-yl)ethanol (859MG, 1.3mmol, 1.00eq., stage 6, example 142 ) in THF (5 ml) is added to the Mitsunobu reagents, followed by the addition of 2-fluoro-4-hydroxybenzoic acid methyl ether (340 mg, 2.0 mmol, 1 equiv.). The resulting solution is stirred overnight. THF is removed. The residue is partitioned between EtOAc and water.

The organic phase is washed with water, saturated salt solution and dried over Ma95O05. The product is purified on a silica gel column using a mixture of 875 E(OAc/hexane. 0.95 g (9090) of the product is obtained as a white solid.

Stage 2: Deprotect 4-(2-71-benzhydryl-2-(2-(tert-butyldiphenylsilanyloxy)ethyl|-5-chloro-1H-indol-3-ylethoxy)-2-fluorobenzoic acid methyl ester according to procedure of example 143, step 9, obtaining 4-2-(1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indole-3-yl|ethoxy)-2-fluorobenzoic acid methyl ester in a yield of 8990 .

Stage C: Methyl ether

4-2-P1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indole-3-yl|ethoxy)-2-fluorobenzoic acid is activated by conversion to mesylate as described in step 10 of example 143, and the resulting as a result, the product is used without purification at the next stage.

Step 4: The mesylate from the previous step is replaced with an azide as described in step 11 of Example 143 to give 4-12-(2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl| of ethoxy)-2-fluorobenzoic acid with a yield of 9795 (in two stages).

Stage 5: The methyl ester of 4-2-(2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)-2-fluorobenzoic acid is reduced under Staudinger conditions to give methyl 70 4 -2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)-2-fluorobenzoate with a yield of 93965.

Stage 6: Perform the interaction of methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)-2-fluorobenzoate from the previous stage with 2-chlorobenzenesulfonyl chloride, respectively to the procedure of Example 1, step 7, giving the desired product in a yield of 73905.

Stage 7: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9695. MS high-resolution calculations. for

ISzvNazyaSI2EM2O55' NNI 717.13876, found 717.1365.

Example 191: 4-(2-71-benzhydryl-5-chloro-2-(2-(2-chloro-6-methylbenzenesulfonylamino)ethyl|-1H-indol-3-ylethoxy)-2-fluorobenzoic acid

Stage 1: This compound is obtained from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indole-3-yl|ethoxy)-2-fluorobenzoate (stage 5, example 190 ) and 2-chloro-β6-methylbenzenesulfonyl chloride by the procedure of example 1, stage 7 with a yield of 6690.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of Example 1, obtaining the acid indicated in the title with a yield of 9595. High-resolution MS calcd. for

ISzeNzzSIEM2O55NI 731.15441, found 731.1532. and)

Example 192:

IM-(2-(1-benzhydryl-5-chloro-3-12-(4-(2H-tetrazol-5-yl)uphenoxy|ethyl)-1H-indol-2-yl)ethyl|-1-(3 ,4-dichlorophenyl)methane sulfonamide with zo Stage 1: Carry out the interaction of 2-(1-benzhydryl-2-(2-(tert-butyldiphenylsilanyloxy)ethyl/|-5-chloro-1H-indol-3-yl)dethanol from stage b of example - 142 with 4-hydroxybenzonitrile under the conditions described in example 189, stage 1, obtaining "g 4-(2-711-benzhydryl-2-(2-(tert-butyldiphenylsilanyloxy)ethyl|-5-chloro-1H- indole-3-yl)oethoxy)benzonitrile with a yield of 8 Boron

Step 2: Deprotect the silyl ether from the previous step according to Example 143, step 9, to give 4-(2-(1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indole-3 -iliethoxy)benzonitrile with a yield of 93965.

Step 3: The alcohol from the previous step is activated by conversion to the mesylate as described in step 10 of example 143, yielding the desired mesylate, which is used without purification in the next step.

Step 4: The mesylate from the previous step is treated under the conditions described in step 11 of Example 143 to give "4-2-(2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indole-3-ilyethoxy)benzonitrile with an output of 9195 (in two stages). Step 5: 4-(2-(2-(2-Azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzonitrile is reduced under Staudinger conditions as detailed in Step 12 example 143, obtaining 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl ethoxy)benzonitrile with a yield of 92965.

Stage 6: 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzonitrile from the previous stage and -I (3,4-dichlorophenyl )methanesulfonyl chloride according to the procedure of Example 1, step 7, to give the desired product in a yield of 92905.

Step 7: A mixture of nitrile (1.O0eq.), azidotrimethylsilane (2.Eq.), dibutyltin oxide (0.Eq.) and toluene (3.3ml/mmol) is heated in a sealed tube at 1202C for 20 hours. The mixture is acidified with HCl at room temperature, then diluted with E(OAc. The organic phase is washed with water and a saturated salt solution,

They are dried over M950, u. Crude tetrazole is subjected to chromatography using a mixture of 5095 E(Ac/hexane -

Kz 80956 E(Ac/hexane plus 0.595 acetic acid to give the title product in 5895 yield. High resolution MS calcd for |C2N22Si2MeO2ANI 771.14732, found 771.1475.

Example 193:

M-2-(1-benzhydryl-5-chloro-3-(2-I4-(2H-tetrazol-5-yl)uphenoxy|ethyl)-1H-indol-2-yl)ethyl)|-2-chlorobenzenesulfonamide

Stage 1: Carry out the interaction of 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl)benzonitrile (stage 5, example 192) and CO2 -chlorobenzenesulfonyl chloride by the procedure of Example 1, step 7, to give the desired product in a yield of 7790.

Step 2: The nitrile from the previous step is converted to the tetrazole according to the procedure of step 7 of Example 192 to give the title product in a yield of 4595. High resolution MS calcd. for

ISzvNaza Si MeOz'ANI 723.17065, found 723.1711.

Example 194:

IM-(2-(1-benzhydryl-5-chloro-3-12-(4-(2nH-tetrazol-5-yl)uphenoxy|ethyl)-1H-indol-2-yl)ethyl|butane-1-sulfonamide

Stage 1: Perform the interaction of 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzonitrile (stage 5, example 192) and 1-butanesulfonyl chloride by the procedure of Example 1, step 7, giving the desired product in a yield of 79965.

Step 2: The nitrile is converted to the tetrazole according to the procedure of step 7 of Example 192 to give the title product in a yield of 9195. High resolution MS calcd. for |С z6Naz7SIMeOzZZZANI 669.24092, found 669.2409,

Example 195:

IM-(2-(1-benzhydryl-5-chloro-3-12-(4-(2H-tetrazol-5-yl)uphenoxy|ethyl)-1H-indol-2-yl)ethylI-2,2,2 -trifluoroethanesulfon amide

Stage 1: Carry out the interaction of 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|Hieethoxy)benzonitrile (stage 5, example 192) and 7/0. of 2,2,2-trifluoroethanesulfonyl chloride by the procedure of Example 1, step 7, to give the desired product in a yield of 6490.

Step 2: The nitrile is converted to the tetrazole according to the procedure of step 7 of Example 192 to give the title product in a yield of 7795. High resolution MS calcd. for |C zANAzoSIRzZMeOZANI 695.18135, found 695.1807.

Example 196: 4-(2-711-benzhydryl-5-chloro-2-(2-(2,4,6-trifluorobenzene-sulfonylamino)ethyl|-1H-indol-3-yl)ethoxy)benzoic acid

Stage 1: This compound is obtained from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and 2 ,4,6-trifluorobenzenesulfonyl chloride by the procedure of example 1, stage 7 with a yield of 92965.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9295. MS high-resolution calculations. for

ISzvNzosSiEM2Oz' ANI 719.15889, found 719.15843.

Example 197: ch 4-(2-71-benzhydryl-5-chloro-2-(2-(4-methoxy-2-nitrobenzenesulfonylamino)ethyl/|-1H-indole-3-ilyethoxy)benzoic acid i)

Stage 1: This compound is obtained from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and 4 -methoxy-2-nitrobenzenesulfonyl chloride by the procedure of Example 1, step 7 in yield 7496. c zo Step 2: The intermediate compound, which is an ester, is hydrolyzed in accordance with step 8 of example 1 to give the title acid in yield 9495. MS of high difference calculation for -

ISZENZASIMZOV'ANI 740.1828, found 740.1834. "IS

Example 198: 4-(2-71-benzhydryl-5-chloro-2-(2-(3-trifluoromethoxybenzene-sulfonylamino)ethyl|-1H-indol-3-yl)ethoxy)benzoic acid

C5 Acid cha

Stage 1: This compound is obtained from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and

C-(trifluoromethoxy)benzenesulfonyl chloride by the procedure of example 1, stage 7 with a yield of 6195.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 8675. MS high-resolution calculations. for shsh with ISzenzoSiezMoov6'ANI 771.1514, found 771.1512. . Example 199: 4-(3-71-benzhydryl-5-chloro-2-(2-(2,4,6-trifluorobenzenesulfonylamino)ethyl|-1H-indol-z3-yl) and»propyl)benzoic acid

Stage 1: To methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6, example 42) is added -trifluorobenzenesulfonyl chloride by the procedure of Example 1, step 7, obtaining -I product in a yield of 6195.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of Example 1, obtaining the acid indicated in the title with a yield of 9795. High-resolution MS calcd. for i5" ISzenzoSiezM2O, ANI 717.17962, found 741.17913.

Example 200:

Ш- 4-(3-71-benzhydryl-5-chloro-2-(2-(4-methoxy-2-nitrobenzenesulfonylamino)ethyl|-1H-indole-3-ylpropyl) benzoin

From acid

Stage 1: 4-Methoxy-2 -nitrobenzenesulfonyl chloride by the procedure of Example 1, step 7, obtaining this product in a yield of 8195.

Step 2: The intermediate, which is an ester, is hydrolyzed according to step 8 (F, Example 1) to give the title acid in a yield of 9595. High resolution MS calcd. 2028.

Example 201: in 4-(3-71-benzhydryl-5-chloro-2-(2-(3-trifluoromethoxybenzene-sulfonylamino)ethyl|-1H-indol-3-yl)ipropyl)benzoic acid

Stage 1: 4-Methoxy-2 -nitrobenzenesulfonyl chloride by the procedure of Example 1, step 7, to give the product in 83905 yield. 65 Step 2: The ester intermediate is hydrolyzed according to Example 1, step 8, to give the title acid in 9195 yield. High resolution MS calcd. . for

ISloNzaSIezZM2OB5 ANI 747.19019, found 747.18996.

Example 202: 4-2-11-benzhydryl-5-chloro-2-12-(I(4-methylsulfonylbenzene)sulfonyl)amino|ethyl)-1H-indol-3-yl)propyl|Ibenzoin

Acid

Step 1: 4-methylsulfonylbenzenesulfonyl chloride is added to methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (Stage 6, Example 42) by the procedure of Example 1, step 7, yielding product 65905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 7/0 of example 1, obtaining the acid indicated in the title with a yield of 10075. MS high-resolution calculations. for

ISloNa7SIMOOv5" ANI 741.18544, found 741.18421.

Example 203: 4-(2-(1-benzhydryl-2-2-((4-methylsulfonylbenzene)amino|ethyl)-5-chloro-1H-indol-3-yl)ethoxy|benzoic acid

Stage 1: This compound is obtained from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and 4 -methylsulfonylbenzenesulfonyl chloride by the procedure of example 1, stage 7 with a yield of 6195.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9095. MS high-resolution calculations. for

ISzenz5SIM2O755-NO 741.15014, found 741.14842.

Example 204: 4-2-11-benzhydryl-5-chloro-2-12-(I(2-methylsulfonylbenzene)sulfonyl)amino|ethyl)-1H-indol-3-yl)propyl|Ibenzoic acid

Stage 1: To methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6, example 42) is added 2-methylsulfonylbenzenesulfonyl chloride by the procedure of the example 1, step 7, giving the solid product in a yield of 6595.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 i) of example 1, obtaining the acid indicated in the title with a yield of 10095. MS high-resolution calculations. for

ISloNaz7SIMOOv5»2 NO 741.18544, found 741.18425.

Example 205: c zo 4-(2-(1-benzhydryl-2-22-((2-methylsulfonylbenzene)amino|ethyl)-5-chloro-1H-indol-3-yl)ethoxy|benzoic acid

Stage 1: This compound is obtained from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and g of 2-methylbenzenesulfonyl chloride by the procedure of example 1, stage 7 with a yield of 61905.

Stage 2: The intermediate compound, which is an ester, is hydrolyzed according to stage 8-

From example 1, obtaining the acid indicated in the title with a yield of 9095. MS high-resolution calculations. for M

ISzenz5SIM2O752 NO 743.16470, found 743.16431.

Example 206: 4-2-11-benzhydryl-5-chloro-2-12-((3-phenylsulfonylbenzene)sulfonyl)amino|ethyl)-1H-indol-3-yl)propyl| benzoic acid

Stage 1: Add 3-phenylbenzenesulfonyl chloride to methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6, from example 42) by the procedure of Example 1, step 7, yielding a product with a yield of 6595. ;" Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 10095. MS high-resolution calculations. for 45. ISa5NazoSIM2O,Z'H) 739.23919, found 739.23896. -I Example 207: 4-(2-(1-benzhydryl-2-2-((3-phenylsulfonylbenzene)amino|ethyl)-5-chloro-1H-indol-3-yl)ethoxy|benzoic acid

Ш- Stage 1: This compound is obtained from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1 ) and

C-phenylbenzenesulfonyl chloride by the procedure of example 1, stage 7 with a yield of 61905.

Sh- Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9095. MS high-resolution calculations. for

ISlaNa7SIMgOBZANI 741.21845, found 741.21879.

Example 208: 4-2-P1-benzhydryl-5-chloro-2-12-I(2-trifluoromethylsulfonyl-benzene)isulfonyl)amino|ethyl)-1H-indol-3-yl)propyl benzoic acid

F) Stage 1: 2- trifluoromethylsulfonylbenzenesulfonyl chloride by the procedure of Example 1, step 7, yielding the product in 6590. in Step 2: The ester intermediate is hydrolyzed in accordance with step 8 of Example 1, yielding the title acid in 10095. High resolution MS calcd. for

ISloNzaEzSIM2OBANI 731.19527, found 731.19591.

Example 209: 4-(2-(1-benzhydryl-2-22-((2-trifluoromethylsulfonylbenzene)amino|ethyl)-5-chloro-1H-indol-3-yl)ethoxy|benzoic acid 65 Stage 1: This compound obtained from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and

2-trifluoromethylbenzenesulfonyl chloride by the procedure of example 1, stage 7 with a yield of 6195.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9095. MS high-resolution calculations. for 5.0 ISkhONzaRzSIM2O4Z NO 733.17454, found 733.17439.

Example 210: 4-(3-P1-benzhydryl-5-chloro-2-(2-S(5-methyl-1-phenyl-1H-pyrazol-4-yl)usulfonylamino)ethyl)-1H-indole-3- il|Ipropyl)b enzoic acid

Stage 1: 5- methyl-1-phenyl-1H-pyrazole-4-sulfonyl chloride by the procedure of Example 1, step 7, to give the product in a yield of 9390.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9995. MS high-resolution calculations. for

ISazNzeSIMAaOa'ANI 743.24533, found 743.24506.

Example 211: 4-2-P1-benzhydryl-5-chloro-2-22-S(5-methyl-1-phenyl-1H-pyrazol-4-yl)usulfonyl)amino)ethyl)-1H-indole-3- il|ethoxy)b enzoic acid

Stage 1: 5-methyl-1 -phenyl-1H-pyrazole-4-sulfonyl chloride by the procedure of Example 1, step 7, 2o to give the product in a yield of 8870.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 10095. MS high-resolution calculations. for

ISl2Na7SIMAOBZANI 745.2246, found 745.22362.

Example 212: sc dv 43-11 -benzhydryl-5-chloro-2-(2-1(1,3,5-trimethyl-1H-pyrazol-4-yl)usulfonylamino)ethyl)-1H-indol-3-yl |Ipropyl)benzoic acid i)

Stage 1: 1,5-dimethyl is added to methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6, example 42) -1H-pyrazole-4-sulfonyl chloride by the procedure of Example 1, Step 7, to give the product in 92905 yield. output 9295. MS of high resolution calculation. for -

ISzenzeSIMAaO,Z'ANI 695.24533, found 695.24453. "IS

Example 213: 4-2-11-benzhydryl-5-chloro-2-(2-X(1,3,5-trimethyl-1H-pyrazol-4-yl)usulfonyl|amino)ethyl)-1H-indole-3 -yl|ethoxy)be i- nzoic acid cha

Stage 1: 1,5-dimethyl is added to methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage 6, example 1) -1H-pyrazole-4-sulfonyl chloride by the procedure of Example 1, step 7, to give the product in a yield of 100905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 7475. MS high-resolution calculations. for shsh with ISzvNa7SIMAOBZANI 697.2246, found 697.2241. . Example 214: and? 4-(3-P1-benzhydryl-5-chloro-2-(2-S((2,3-dichlorophenyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|propyl)ubenzoic acid

Stage 1: 2,3-dichlorobenzenesulfonyl chloride is added to methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6, example 42) by the procedure of Example 1, step 7, giving the product with -I yield 8595.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of Example 1, obtaining the acid indicated in the title with a yield of 9695. High-resolution MS calcd. for і5» ISzeNzzSiIzM20.5-NI 729.1154, found 729.1135.

Example 215:

Ш- 4-(2-P1-benzhydryl-5-chloro-2-(2-Ш((2,3-dichlorophenyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid

Ge Stage 1: 2,3- dichlorobenzenesulfonyl chloride by the procedure of Example 1, step 7, to give the product in a yield of 7995.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9795. MS high-resolution calculations. for (F, ISzvNazyaiSizM2O55-NI 731.0947, found 731.0930. ka Example 216: 4-(3-P1-benzhydryl-5-chloro-2-(2-C(4-fluoro-1,1"-diphenyl -4-yl)usulfonyl|amino)ethyl)-1H-indol-3-yl|Ipropyl)ubenzoic acid

Stage 1: 4"-Fluorophenyl- 4-benzenesulfonyl chloride by the procedure of Example 1, step 7, to give the product in a yield of 65905.

Stage 2: The intermediate compound, which is a complex zephyr, is hydrolyzed in accordance with stage 8 b5 of example 1, obtaining the acid indicated in the title with a yield of 10095. High-resolution MS calcd. for

ISl5NzvSieM20, ANI 757.22976, found 757.22874.

Example 217: 4-2-11-benzhydryl-5-chloro-2-(2-CH(4-fluoro-1,1"-diphenyl-4-yl)usulfonyl|iamino)ethyl)-1H-indole-3- yl|Iiethoxy)benzoic acid

Stage 1: This compound is obtained from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and 4 -fluorophenyl-4-benzenesulfonyl chloride by the procedure of example 1, stage 7 with a yield of 61905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9095. MS high-resolution calculations. for 70. ISlaNzeSIEM2O5Z'NI 759.20903, found 759.20745.

Example 218: 4-2-11-benzhydryl-5-chloro-2-12-I(3-trifluoromethylbenzene)sulfonyl)amino|ethyl)-1H-indol-3-yl)ipropyl| benzoic acid

Stage 1: 3-trifluoromethylbenzenesulfonyl chloride is added to methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6, /5 example 42) by the procedure of Example 1, step 7, yielding product 65905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 10095. MS high-resolution calculations. for

ISloNaUSiezZMoO, Z'ANI 731.19527, found 731.19582.

Example 219: 4-(2-(1-benzhydryl-2-22-((3-trifluoromethylbenzene)amino|ethyl)-5-chloro-1H-indol-3-yl)ethoxy|benzoic acid

Stage 1: This compound is obtained from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and

3-trifluoromethylbenzenesulfonyl chloride by the procedure of example 1, stage 7 with a yield of 6190. s

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9095. MS high-resolution calculations. for i)

ИзеНз5СиезМ2О58 NO 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 with zo Stage 1: To methyl 4-2-/1-benzhydryl-5-chloro-2-(2-chloromethanesulfonylaminoethyl)-1H-indole-3-yl ethoxy)benzoate, example 81, stage - 1, add 3 ,4-dichlorothiophenol by the procedure of example 81, stage 2. The crude substance is purified by preparative HPLC with a yield of ester 24905 and acid 1490.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9790. t/2 (M-1) 779.01. M

Example 221: 4-(2-(1-benzhydryl-5-chloro-2-12-IC(3-chloro-4-fluorophenyl)thio|methyl)isulfonyl)amino|ethyl)-1H-indol-3-yl) ethoxy) benzoic acid

Stage 1: To methyl "4-2-/1-benzhydryl-5-chloro-2-(2-chloromethanesulfonylaminoethyl)-1H-indol-3-ilyethoxy)benzoate, example 81, stage c 1, add 3-chloro- 4-fluorothiophenol by the procedure of example 81, stage 2. The product is purified with a column. by flash chromatography using a mixture of 3090 E(UAc/hexanes with a yield of 70905. i?" Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 89905. pt /2 (M-1) 760.94.

Example 222: -I 4-(2-(1-benzhydryl-5-chloro-2-12-IC2-fluorobenzene)sulfonyl)amino|ethyl)-1H-indol-3-yl)/propyl|b Phenzoic acid

Stage 1: To methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6,

Ш- example 42) add 2-fluorobenzenesulfonyl chloride by the procedure of example 1, stage 7, obtaining a product with a yield of 6595.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of Example 1, obtaining the acid indicated in the title with a yield of 10095. High-resolution MS calcd. for

681.19846 of ISZENZASIEM20.5 ANI, found 699.19854.

Example 223: 4-(2-(1-benzhydryl-2-(2-((2-fluorobenzene)amino|ethyl)-5-chloro-1H-indol-3-yl)ethoxy|benzoic acid

Stage 1: This compound is obtained from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and

Ф) of 2-fluorobenzenesulfonyl chloride by the procedure of Example 1, stage 7 with a yield of 6195. ka Stage 2: The intermediate compound, which is an ester, is hydrolyzed according to stage 8 of Example 1, obtaining the acid indicated in the title with a yield of 9095. High-resolution MS calcd. . for in ISzvNzzSIeMoOB5Z'NI 683.17773, found 683.17694.

Example 224: 4-(2-(1-benzhydryl-5-chloro-2-12-((2,6-difluorobenzene)isulfonyl)amino|ethyl)-1H-indol-3-yl)ipropyl|Isenzoic acid

Stage 1: 2,6-difluorobenzenesulfonyl chloride is added to methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6, example 42) by the procedure of Example 1, step 7, to give product 65 in a yield of 65905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 10095. MS high-resolution calculations. for

ISzeNzzSIg2M20, ANI 699.18904, found 699.18850.

Example 225: 4-(2-(1-benzhydryl-2-2-((2,6-difluorobenzene)amino|ethyl)-5-chloro-1H-indol-3-yl)ethoxy|benzoin

Acid

Stage 1: This compound is obtained from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and 2 ,6-difluorobenzenesulfonyl chloride by the procedure of example 1, stage 7 with a yield of 6195.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 7/0 of example 1, obtaining the acid indicated in the title with a yield of 9075. MS high-resolution calculations. for

ISzvNazoSig2M2O5 ANI 701.16831, found 701.16849.

Example 226: 4-(2-(1-benzhydryl-5-chloro-2-12-I(I(2-chloro-6-methylbenzene)sulfonyl)amino|ethyl)-1H-indol-3-yl)propyl| benzoic acid

Stage 1: 2-Chloro-6 -methylbenzenesulfonyl chloride by the procedure of Example 1, step 7, to give the product in a yield of 65905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 10095. MS high-resolution calculations. for 20. ISaoNzeSi2M20u5'ANI 711.18456, found 711.18404.

Example 227: 4-(2-(1-benzhydryl-2-2-((2-chloro-6-methylbenzene)amino|ethyl)-5-chloro-1H-indol-3-yl)ethoxy|benzoic acid

Stage 1: This compound is obtained from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and 2-chloro-β6-methylbenzenesulfonyl chloride by the procedure of example 1, stage 7 with a yield of 61965.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 i) of example 1, obtaining the acid indicated in the title with a yield of 9095. MS high-resolution calculations. for

ISZENZASI2M2O55NI 713.16383, found 713.16269.

Example 228: c zo 4-(2-(1-benzhydryl-5-chloro-2-12-I(4-trifluoromethylbenzene)sulfonyl)amino|ethyl)-1H-indol-3-yl)ipropyl|Senzoic acid -

Stage 1: 4-trifluoromethylbenzenesulfonyl chloride is added to methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6, example 42) by the procedure of Example 1, step 7, giving the product with a yield of 65905. -

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of Example 1, obtaining the acid indicated in the title with a yield of 10095. High-resolution MS calcd. for

ISloNaUSiezZMoO, Z'ANI 731.19527, found 731.19580.

Example 229: 4-(2-(1-benzhydryl-2-2-((4-trifluoromethylbenzene)amino|ethyl)-5-chloro-1H-indol-3-yl)ethoxy|Ibenzoic acid "

Stage 1: This compound is obtained from methyl c 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and 4-trifluoromethylbenzenesulfonyl chloride by the procedure of example 1, step 7 in a yield of 6195. i?" Step 2: The intermediate compound, which is an ester, is hydrolyzed in accordance with step 8 of example 1, obtaining the acid indicated in the title in a yield of 9095. MS of high calculated resolution for 45. ISzenzvSIgzM2O5'ANI 733.17454, found 733.17432. -I Example 230: 4-(2-(1-benzhydryl-5-chloro-2-12-I(2-trifluoromethoxybenzene)sulfonyl)amino |ethyl)-1H-indol-3-yl)propyl|bSenzoic acid their Stage 1: To methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indole-Z -yl|propyl)benzoate (stage 6, 5r example 42) is added with 2-trifluoromethoxybenzenesulfonyl chloride by the procedure of example 1, stage 7, obtaining the product with a yield of 65905.

Ge Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 10095. MS high-resolution calculations. for

ISLONZU SIEZMOOBZANI 747.19019, found 747.18848.

Example 231: 4-(2-(1-benzhydryl-2-42-((2-trifluoromethoxybenzene)amino|ethyl)-5-chloro-1H-indol-3-yl)ethoxy|benzoic acid

F) Stage 1: This compound is obtained from methyl ka 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1 ) and 2-trifluoromethoxybenzenesulfonyl chloride by the procedure of Example 1, step 7 with a yield of 6190. in Step 2: The intermediate, which is an ester, is hydrolyzed according to step 8 of Example 1 to give the title acid with a yield of 9095. High-resolution MS calcd. . for

ISzeNz5SIezMoOv6 ANI 749.16945, found 733.16813.

Example 232: 4-(2-(1-benzhydryl-5-chloro-2-12-I(2-methylbenzene)sulfonyl)amino|ethyl)-1H-indol-3-yl)propyl benzoic acid 65 Stage 1: To methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6, example 42) add 2-methylbenzenesulfonyl chloride by the procedure of example 1, stage 7 , yielding a product with a yield of 6595.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 10095. MS high-resolution calculations. for 5. IShoNaSIM2O)Z NO 677.22354, found 677.22244.

Example 233: 4-(2-(1-benzhydryl-2-2-((2-methylbenzene)amino|ethyl)-5-chloro-1H-indol-3-yl)ethoxy|benzoic acid

Stage 1: This compound is obtained from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and 70 of 2-methylbenzenesulfonyl chloride by the procedure of example 1, stage 7 with a yield of 61905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9095. MS high-resolution calculations. for

ISzenz5SIM2OB ANI 679.20280, found 679.20197.

Example 234: 4-(2-(1-benzhydryl-5-chloro-2-12-(I(2-methoxybenzene)sulfonyl)amino|ethyl)-1H-indol-3-yl)/propyl|bSenzoic acid

Step 1: 2-Methoxybenzenesulfonyl chloride is added to methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (Step 6, Example 42) by the procedure of Example 1, step 7, giving the product in yield 6595.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 10095. MS high-resolution calculations. for

ISloNa7SIM2OBZ ANI 693.2185, found 693.21852.

Example 235: 4-I(2-(1-benzhydryl-2-(2-I(2-methoxybenzene)amino|ethyl)-5-chloro-1H-indol-3-yl)ethoxy|benzoic acid

Stage 1: This compound is obtained from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and 2-methoxybenzenesulfonyl chloride by the procedure of example 1, stage 7 with a yield of 61965. i)

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9095. MS high-resolution calculations. for

ISzenz5SIM2O 65 ANI 695.19722, found 695.19701. Example 236: 4-(2-(1-benzhydryl-5-chloro-2-12-(1(2-tert-butylbenzene)sulfonyl)amino|ethyl)-1H-indol-3-yl)propyl| benzoic acid "E

Stage 1: 2-tert-butylbenzenesulfonyl chloride is added to methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6, example 42) by the procedure of example 1, stage 7, obtaining the product y- with a yield of 65905. M

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 10095. MS high-resolution calculations. for

ISazNazSIM2O,Z'ANI 719.27049, found 719.27057.

Example 237: « 40. 4-I2-(1-benzhydryl-2-(2-(2-tert-butylbenzene)amino|ethyl)-5-chloro-1H-indol-3-yl)ethoxy|benzoic acid in Stage 1: This compound is obtained from methyl. 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and i» of 2-tert-butylbenzenesulfonyl chloride by the procedure of example 1, stage 7 with output 6195.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9075. MS high-resolution calculations. for -I ISlg On SIM BANI 721.24975, found 721.24907.

Example 238:

Ш- 4-(2-(1-benzhydryl-5-chloro-2-12-I(2-methylthiobenzene)isulfonyl)amino|ethyl)-1H-indol-3-yl)ipropyl|Senzoic acid their Stage 1: To methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6, 5r example 42) add 2-methylthiobenzenesulfonyl chloride by the procedure of example 1, stage 7, giving a product with a yield of 6595.

Ge Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 10095. MS high-resolution calculations. for

ISloNaz7SIM2O 52 NO 709.19561, found 709.19504.

Example 239: 4-(2-(1-benzhydryl--2-(2-((2-methylthiobenzene)amino|ethyl)-5-chloro-1H-indol-3-yl)ethoxy|benzoic acid

F) Stage 1: This compound is obtained from methyl ka 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1 ) and 2-methylthiobenzenesulfonyl chloride by the procedure of Example 1, step 7 in a yield of 61905. in Step 2: The ester intermediate is hydrolyzed according to step 8 of Example 1 to give the title acid in a yield of 9095. High resolution MS calcd. . for

ISzenz5SIM2Ov" NO 711.17487, found 711.17518.

Example 240: 4-(2-(1-benzhydryl-5-chloro-2-12-((3-chloro-2-methylbenzene)sulfonyl)amino|ethyl)-1H-indol-3-yl)ipropyl|bSenzoic acid 65 Stage 1: 3-chloro- 2-methylbenzenesulfonyl chloride by the procedure of Example 1, step 7, to give the product in a yield of 65905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 10095. MS high-resolution calculations. for 5. IShoNzeSi2M2OuZ'N) 711.18456, found 711.18465.

Example 241: 4-(2-(1-benzhydryl-2-2-((3-chloro-2-methylbenzene)amino|ethyl)-5-chloro-1H-indol-3-yl)ethoxy benzoic acid

Stage 1: This compound is obtained from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and 70 C-chloro-2-methylbenzenesulfonyl chloride by the procedure of example 1, stage 1 with a yield of 61905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9095. MS high-resolution calculations. for

ISZENZASI2 MOB" NO 713.16383, found 713.16296.

Example 242: 4-(2-(2-2-(2-(4-acetylpiperazin-1-yl)ethanesulfonylamino|ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl)ethoxy benzoic acid

Step 1: The compound was prepared in yield 9195 from the intermediate of Example 100, Step 1 and 1-acetylpiperazine by the procedure of Example 100, Step 2, except that the mixture was heated at 60 F for 19 hours.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 19905. t/2 (M-1) 741.2.

Example 243: 4-(2-(1-benzhydryl-5-chloro-2-12-(2-(3,5-dimethylpiperazin-1-yl)ethanesulfonylamino|ethyl)-1H-indol-3-yl)ethoxy benzoin acid with

Step 1: The compound was prepared in yield 9795 from the intermediate of Example 100, Step 1 and cis-2,6-dimethylpiperazine by the procedure of Example 100, Step 2, except that the mixture was heated at 602° for 19 hours.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 39905. t/2 (M-1) 727.2. Ge

Example 244: 4-(2-(2-2-(2-(4-acetyl-3,5-dimethylpiperazin-1-ylluethanesulfonylamino|ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl) et toxy|benzoic acid "I

Stage 1: To a solution of methyl ether 4-(2-(1-benzhydryl-5-chloro-2-12-(2-(3,5-dimethylpiperazin-1-yl)ethanesulfonylamino|ethyl)-1H-indole-3- yl)ethoxy|ben -

ZOOYNOIic acid (stage 1, previous example) (Zimg, O0.042mmol) in CHCl (1ml) at 09C is added EBM (0.10ml) /zcha and AsoO (bOmcl) and the reaction mixture is stirred at room temperature for 4 hours. Treatment with water followed by chromatography on silica gel (3.590 Meon/Meon) afforded the desired ester intermediate (17mg, yield 5296). "

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 96905. t/2 (M-1) 771.2. - with Example 245: 4-(2-71-benzhydryl-5-chloro-2-(2-(42-(4-methylpiperidin-1-yl)a ethyl|sulfonyl)amino)ethyl/|-1H-indol- 3-ylethoxy)benzoic acid"" Step 1: The compound is prepared from the intermediate of Example 100, Step 1 and 1-acetylpiperazine 4-methylpiperidine by the procedure of Example 100, Step 2. The product is purified by flash column chromatography using a mixture of 50-60956 EtOAc/Hexane with a yield of 87905. -and Stage 2: The intermediate, which is an ester, is hydrolyzed in accordance with step 8-1 of Example 1, except that the pH is adjusted to 4-5, obtaining the title acid with a yield of 91905. t/2 (M-1) 712.3.

ChK" Example 246: 4-(2-71-benzhydryl-5-chloro-2-(2-(42-(3-methylpiperidin-1-yl)-150 ethyl|sulfonyl)amino)ethyl/|-1H- indole-Z-iliethoxy)benzoic acid

Step 1: The compound is prepared from the intermediate of Example 100, Step 1 and 3-methylpiperidine by the procedure of Example 100, Step 2. The product is purified by flash column chromatography using a mixture of 50-6090

EtOAc/hexane to yield 9495.

Step 2: The ester intermediate is hydrolyzed in accordance with step 8 of example 1, except that the pH is adjusted to 4-5 to give the title acid in a yield of 8795. High resolution MS calcd. for (SloNa«SIMAZO5'ANI 714.2763, found 7142765.

Example 247: imi) 4-(2-(1-benzhydryl-2-(2-(2-(2-carbamoylpyrrolidin-1-ylluethanesulfonylamino|ethyl)-5-chloro-1H-indol-3-yl)ethoxy|ben zoic acid 60 Step 1: The compound is prepared from the intermediate of Example 100, Step 1 and Y-prolinamide by the procedure of Example 100, Step 2. The product is purified by flash column chromatography using EtOAc in 8690 yield.

Step 2: The ester intermediate is hydrolyzed in accordance with step 8 of example 1, except that the pH is adjusted to 4-5 to give the title acid in a yield of 4390 after preparative HPLC. MS of high resolution calculations. for |C z9NSIMAO6ZANI 729.2508, 65 729.251 were found.

Example 248:

4-(2-(1-benzhydryl-5-chloro-2-12-(C2-(28)-2-(methoxymethyl)pyrrolidin-1-yl|ethyl)isulfonyl)amino|ethyl)-1H-indole-3 -yl)ethoxy|benzoic acid

Step 1: The compound is prepared from the intermediate of Example 100, Step 1 and (5)-(4)-2-(methoxymethyl)pyrrolidine by the procedure of Example 100, Step 2. The product is purified by flash column chromatography using a mixture of 8090 E(UAc/hexane with output 87905.

Step 2: The ester intermediate is hydrolyzed in accordance with step 8 of Example 1 except that the pH is adjusted to 4-5 to give the title acid in a yield of 8790.

MS of high resolution calculations. for (SloNaySimzOvZanI 730.2712, found 730.2709. 70 Example 249: 4-(2-71-benzhydryl-5-chloro-2-(2-412-(2-ethylpiperidin-1-yl)ethylsulfonylamino)ethyl |-1H-indol-3-yl)ethoxy)benzoic acid

Step 1: The compound is prepared from the intermediate of Example 100, Step 1 and 2-ethylpiperidine by the procedure of Example 100, Step 2. The product is purified by flash column chromatography using a mixture of 50-6090

EtOAc/hexane to yield 73905.

Step 2: The ester intermediate is hydrolyzed in accordance with step 8 of example 1 except that the pH is adjusted to 4-5 to give the title acid in a yield of 3890 after purification by preparative HPLC. MS of high resolution calculations. for |C 4Na6SIMzOBZANI 728.292, found 728.2925.

Example 250: 4-(2-(1-benzhydryl-5-chloro-2-12-(C2-(ZC,55)-3,5-dimethylmorpholin-4-yl|1-ethylsulfonyl)amino|ethyl)-1H-indole -3-yl)ethoxy)| benzoic acid

Step 1: The compound is prepared from the intermediate of Example 100, Step 1 and cis-2,6-dimethylmorpholine by the procedure of Example 100, Step 2. The product is purified by flash column chromatography using a 5095 mL EtOAc/hexane mixture to yield 79905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 i) of example 1, except that the pH is adjusted to 4-5, obtaining the acid indicated in the title with a yield of 94906. t/2 (M-1 ) 729.4.

Example 251: c zo 4-(2-71-benzhydryl-5-chloro-2-(2-(12-(2-oxa-5-azabicyclo|2.2.1)hept-5-yl)ethyl|isulfonylamino)ethyl |-1H-indol-3-yl)ethoxy)benzoic acid -

Step 1: The compound is prepared from the intermediate of Example 100, Step 1 and (15,45)-(4)-2-aza-5-oxabicyclo-|2.2.11-heptane hydrochloride by the procedure of Example 100, Step 2. The product is purified on SotrbiRiazy with a mixture of 1-790 Meon/SNeoSii" with a yield of 85905. -

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of Example 1, except that the pH is adjusted to 4-5, obtaining the acid indicated in the title with a yield of 10095. High resolution MS calcd. for (Sz9NaoSIMazOv5'ANI 714.2399, found 714.2397.

Example 252: 4-(2-711-benzhydryl-5-chloro-2-(2-(2-(2-isopropylpyrrolidin-1-yl)ethylsulfonylamino)ethyl|-1H-indol-3-yl)ethoxy « ) benzoin acid in c Stage 1: The compound is obtained from the intermediate compound of example 100, stage 1 and 2-(methylethyl)pyrrolidine. hydrochloride by the procedure of example 100, stage 2. The product is purified for Sotrigiasis with a mixture of 1-590 and Meon/sn.esi" with a yield of 6195.

Stage 2: The intermediate compound, which is an ester, is hydrolyzed in accordance with stage 8 of example 1, except that the pH is adjusted to 4-5, obtaining the acid indicated in the title with a yield of 9770. -And MS high-resolution calculations. for (S44NavSIMa3O5Z'ANI 728,292, found 728,293.

Example 253:

Ш- 4-(2-711-benzhydryl-5-chloro-2-(2-(42-(2-methyl-3-oxopiperazin-1-yl)ethyl|sulfonyl)amino)ethylI-1H-indole-3- il)eto i5» xy) benzoic acid

Step 1: The compound is prepared from the intermediate of example 100, step 1 and 3-methyl-2-piperazinone

Ш- procedure of example 100, stage 2. The product is purified by flash column chromatography using a mixture of 5906 MeOH/CH»oCI» with a yield of 80905.

Step 2: The ester intermediate is hydrolyzed according to step 8 of example 1 except that the pH is adjusted to 4-5 to give the title acid in a yield of 2990 v After purification by preparative HPLC. MS of high resolution calculations. for (C z9NASIMAOvZANI 729.2508, found 729.2501.

F) Example 254: 4-13-(/1-benzhydryl-5-chloro-2-(2-1(2-chlorophenyl)sulfonyl|amino)ethyl)-1H-indol-3-yl| propyl) and benzoic acid

Stage 1: 2-chlorobenzenesulfonyl chloride is added to methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6, because example 1) by the procedure of Example 1, step 7, yielding product 6695. "H NMR (400 MHz, SOCI3) 5 ppm 1.94 (m, 2H), 2.74 (m, 6H), 2.97 (m, 2H ), 3.91 (s, ZN), 4.94 (t, 9U-6.32Hz, 1H), 6.48 (d, 9U-9.09HzC, 1H), 6.79 (dd, U-8 .84, 2.02Hz, 1H), 6.83 (s, 1H), 7.03 (m, 4H), 7.26 (m, 9H), 7.39 (d, U-2.02Hz, 1H ), 7.44 (d, 9U-3.54Hz, 2H), 7.90 (d, 9U-7.58Hz, 1H), 7.96 (d, U-8.34Hz, 2H).

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 65 of example 1, obtaining, after flash chromatography, the acid indicated in the title with a yield of 8495. "H NMR (400 MHz, SOCI5) 5 ppm. 1.96 (m, 2H), 2.76 (m, 6H), 2.98 (m, 2H), 5.00 (t, 9U-6.32Hz, 1H), 6.79 (dd, 9U- 8.84,

2.02Hz, 1H), 6.84 (s, 1H), 7.04 (m, 4H), 7.28 (m, TON), 7.40 (d, 9-1.77Hz, 1), 7 .45 (d, 9U-3.79Hz, 2H), 7.90 (d, 9U-7.59Hz, 1H), 8.02 (d, U-8.34Hz, 2H). MS of high resolution calculations. for |C z9NzySI»M2O,5.Ma| 719.1514, found (ERI-) 695.15363.

Example 255: 4-2-11-benzhydryl-5-chloro-2-(2-S(2-chlorophenyl)sulfonyl|amino)ethyl)-1H-indole-3-ilyethoxy)benzoic acid

Step 1: This compound is prepared from methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate and 2-chlorobenzenesulfonyl chloride by the procedure of example 1, step 7 with yield 86905. "IN nMR (400MHz, DMSO-av) 6 ppm 2.93 (m, 2H), 3.02 (m, 70. 2H), 3.11 (t, 9U-6.57Hz . -8.84, 2.02Hz, 1H), 6.96 (d, U-8.84Hz, 2H), 7.01 (s, 1H), 7.04 (dd, U-6.95, 2, 40Hz, 4H), 7.34 (m, 5H), 7.40 (m, 1), 7.60 (m, ZN), 7.80 (dd, 9U-7.83, 1.52HzC, 1H) , 7.86 (d, U-8.84Hz, 2H), 8.11 (t, U-5.81Hz, 1H).

Stage 2: The intermediate compound, which is an ester, is hydrolyzed in accordance with stage 8 of example 1. The crude substance is purified by flash chromatography, obtaining the acid indicated in the title with a yield of 74965. "YAN NMR (400 MHz, SOSI) 5 ppm 2.89 (m, 2H), 3.18 (t, 9-6.57Hz, 2H), 4.20 (t, 9-6.57Hz, 2H), 5.09 (t, 9U-6, 32Hz, 1H), 6.53 (d, U-8.84Hz, 1H), 6.82 (m, ЗН), 6.90 (s, 1H), 7.05 (m, 4H), 7.26 (m, 7H), 7.45 (m, 2H), 7.52 (d, 9-2.02Hz, 1H), 7.90 (m, 1H), 8.00 (d, U-8.84Hz , 2H).MS of high resolution calculation for

SzvNza Si» Mov 698.1409, found (ERY) 699.14786. Elem, analysis, calculus. for C zaNaoSioMoOvB5: C 65.23; H 4.61; M 4.00; found: C 65.02; H 4.44; M 3.94.

Example 256: 4-(12-(/1-benzhydryl-5-chloro-2-(2-((2-chlorophenyl)sulfonyl|aminoethyl)-1H-indol-3-yl|ethyl)sulfonyl)benzoic acid

Stage 1: This compound is obtained from the methyl ester of 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indole-3-yluiestanesulfonyl)benzoic acid and E 29 2-chlorosulfonyl chloride by the procedure of example 1 , stage 7 with yield 4895. "H NMR (400MHz, SOSI") 5 ppm 2.88 Ge) (q., 9U-7.07Hz, 2H), 3.03 (t, 9U-7.33Hz , 2H), 3.20 (m, 2H), 343 (m, 2H), 3.97 (s, ЗН), 5.18 (t, U-6.44Hz, 1H), 6.46 (d, 9U-8.84Hz, 1H), 6.78 (dd, U-8.97, 2.15Hz, 1H), 6.84 (s, 1H), 7.04 (dd, U-6.69, 2 ,40Hz, 4H), 7.21 (d, 9-2.02Hz, 1H), 7.31 (m, 7H), 7.48 (d, 9U-3.79Hz, 2H), 7.91 (d , U-7.58Hz, 1H), 8.08 (d, 9U-8.59Hz, 2H), 8.24 (m, 2H).

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9795. "H NMR (400 MHz, SOSIS) 5 ppm 2.88. sq., 9U-6.91Hz, 2H), 3.04 (t, 9U-7.20Hz, 2H), 3.22 (m, 2H), 3.45 (m, 2H), 5.25 (t , U-6.44Hz, 1H), 6.47 (d, « 399.09Hz, 1), 6.78 (dd, U-8.84, 2.02Hz, 1H), 6.84 (s, 1H ), 7.04 (dd, 9U-6.57, 2.53Hz, 4H), 7.22 (d, 9-2.02Hz, 1H)U, 7.31 (m, 7H), 7.48 ( d, 9U-3.79Hz, 2H), 7.92 (d, U-7.83Hz, 1H), 8.12 (d, U-8.59Hz, 2H), 8.28 (d, 9U-8 ,34Hz, 2H) and -

Example 257: 4-(3-P1-benzhydryl-5-chloro-2-(2-S(1,2-dimethyl-1H-imidazol-4-yl)usulfonyl|amino)ethyl)-1H-indole- C-yl|propyl) benzoic acid

Stage 1: 1,2-dimethylimidazole-4-sulfonyl chloride is added to methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)ubenzoate by the procedure of the example 1, stage 7, obtaining a product with a yield of « 8090. TN NMR (400 MHz, DMSO-Ov) 5 ppm 1.86 (m, 2H), 2.18 (s, ЗН), 2.71 (m, 4H), 2.94 (m, 4H), 3.49 (s, in s ЗН), 3.83 (s, ЗН), 6.42 (d, U-8.84Хц, 1Н), 6.76 (dd, -4-8.84, 2.02Hz, 1), 7.06 (m, 4H), 7.36 (m, 8H), 7.44 and (d, 9-2.02Hz, 1H) , 7.49 (s, 1H), 7.59 (s, 1H), 7.87 (d, U-8.08Hz, 2H). "" Stage 2: The intermediate compound, which is an ester, is hydrolyzed in corresponding to step 8 of example 1, obtaining the acid indicated in the title with a yield of 6195. "H NMR (400 MHz, DMSO-Ob) 5 ppm 1.87 (m, 2H), 2.18 (s, ЗН), 2 .70 (t, 9U-7.58Hz, 4H), 2.95 (m, 4H), 3.49 (s, ЗН), 6.42 (d, 9U-8.84Hz, 1H), 6.76 (dd, -i 3-8.84, 2.02HZ, 71H), 7.06 (m, 5H), 7.35 (m, 8H), 7.44 (d, 9U-2.02HZ, 1H) , 7.49 (s, 1H), 7.59 (t, 9U-4.93Hz, - 1H), 7.85 (d, U-8.34Hz, 2H). ,5 680.2224, found (ERIF) 681, 22879. Example 258: -1 50 4A-2-11-benzhydryl-5-chloro-2-(2-X((1,2-dimethyl-1H-imidazole-4 -yl)usulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benz propyl acid) Step 1: This compound is prepared from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl) -5-chloro-1H-indol-3-yl|ethoxy)benzoate and 1,2-dimethylimidazole-4-sulfonyl chloride by the procedure of example 1, stage 7 with a yield of 8495. "H NMR (400 MGu,

SOS) b mod. 2.25 (s, ЗН), 3.07 (m, 2Н), 3.13 (m, 2Н), 3.18 (t, 9У-6.82HzС, 2Н), 3.39 (s, ЗН) , 3.88 (c, ZN),

GF! 4.17 (t, 9-6.69Hz, 2H), 5.30 (m, 9U-2.78Hz, 1H), 6.47 (d, 9-9.09Hz, 1H), 6.79 (dd , U-8.84, 2.02Hz, 1H), 6.83 (d, --8.84Hz, 2H), 6.93 (s, 1H), 7.08 (m, 5H), 7.29 (m, 6H), 7.51 (d, 9-2.02Hz, 1H), 7.94 (d, U-8.84Hz, 2H). o Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 5595. "H NMR (400 MHz, DMSO-Ov) 5 ppm 2.17 60 (s, ЗН), 3.02 (m, 9U-910HZ, 4Н), 3.14 (t, 9У-6.57HZ, 2Н), 3.47 (s, ЗН), 4.21 (t, U -669Hz, 2H), 6.47 (d, 3-8.84Hz, 1), 6.79 (dd, U-8.84, 2.27Hz, 1H), 6.96 (d, 9U-8, 84 Hz, 2H), 7.07 (m, 5H), 7.36 (m, 6H), 7.49 (s, 1H), 7.63 (m, 2H), 7.84 (d, U-8 ,84Hz, 2H).High resolution MS calculated for Ca7NzvSiMaO55 682.2017, found (ERikK) 683.20812.

Example 259: bo 3-I4-(42-(/1-benzhydryl-5-chloro-2-(2-1(2-chlorophenyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|IIethyl)isulfonyl )phenyl)

propionic acid

Stage 1: This compound is obtained from 3-(4-12-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indole-3-ylethanesulfonyl)phenyl)propionic acid ethyl ether and 2-chlorosulfonyl chloride by the procedure of example 1, stage 7 with a yield of 7890. "H NMR (400MHz, SOSI"5) 5 ppm 1.25 (m, ЗН), 2.66 (t, 9U-7.58Hz, 2Н), 2, 88 (sq., U-6.48Hz, 2H), 3.07 (m, 6H), 3.34 (m, 2H), 4.12 (sq., U-7.07Hz, 2H), 5, 31 (t, 9U-6.32Hz, 1H), 645 (d, U-8.84Hz, 1H), 6.77 (dd, 9U-8.84, 2.02Hz, 1H), 6.85 (s , 1H), 7.04 (m,

AN), 7.16 (d, 9U-1.77Hz, 1H), 7.30 (m, 7H), 7.46 (m, 4H), 7.91 (m, ЗН).

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 70 of example 1, obtaining after flash chromatography the acid indicated in the title with a yield of 4195. "H NMR (400 MHz, SOCI5) 5 ppm 2, 74 (s, 4H), 2.86 (t, 9U-6.69Hz, 2H), 2.93 (m, 2H), 3.08 (t, 9U-6.57Hz, 2H), 3.29 ( m, 2H), 6.43 (d, 9U-8.84 Hz, 1H), 6.61 (s, 1H), 6.78 (m, 2H), 7.00 (m, 4H), 7.25 (m, 7H), 7.36 (d, 9U-1.77Hz, МН), 7.45 (m, 2H), 7.50 (d, 9U-8.34Hz, 2H), 7.80 (d .

Example 260: 4-22-P1-benzhydryl-5-chloro-2-(2-1(3-chloro-4-methylphenyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid

Stage I: This compound is prepared from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate and 3-chloro-4-methylbenzenesulfonyl chloride by the procedure of example 1, stage 7 with an output of 10095. "H NMR (400 MHz,

SOSIZ) 5 m.d. 2.38 (s, ZN), 2.92 (sq., U-6.99Hz, 2H), 3.09 (t, 9U-7.58Hz, 2H), 3.18 (t, U-644Hz, 2H), 3.88 (s, ZN), 4.21 (t, 9U-644Hz, 2H), 4.42 (t, 9U-644Hz, 1H), 6.54 (d, uU-8.84Hz, 71H), 6.79 (m, 2H), 6.83 (dd, 3-8.84, 2.02Hz, 71), 6.88 (s, 1H), 7.04 (m, 4H), 7 .20 (d, 9U-8.08HZ, 1H), 7.29 (m, 6H), 7.40 (dd, 9U-7.96, 1.89HZ, 1), 7.52 (d, 9- 2.02Hz, 1H), 7.66 (d, 9U-1.77Hz, 1H), 7.93 (m.2H). ch 29 Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 Go) of example 1. The crude product is purified by flash chromatography, obtaining the acid indicated in the title with a yield of 6995. ppm 2.38 (s, ZN), 2.93 (m, 2H), 3.10 (t, 9-7.45 Hz, 2H), 3.19 (t,

U-6.44Hz, 2H), 4.23 (t, 9U-6.44Hz, 2H), 4.52 (s, 1H), 6.54 (d, 9-8.84Hz, 1H), 6, 83 (m, ZN), 6.89 (s, 1H), 7.04 s zo (m, 4H), 7.20 (d, U-8.08Hz, 1H), 7.29 (m, 6H) , 7.40 (dd, 9U-8.08, 1.77Hz, 1H), 7.53 (d, 9U-2.02Hz, 1H), 7.67 (d, 9U-2.02Hz, 1H), 7.98 (d, U-8.84Hz, 2H). MS of high resolution calculations. for С 59Н34СиоМоОБЗ 712.1565, v. found (ERYx) 713.16268. E. anal. calculation for Cz9H534Si»oMoOv5O: C, 65.64; H, 4.80; M, 3.93. Found: C, "t 65,62; H, 4.52; M, 3.73.

Example 261: c. 4-(3-P1-benzhydryl-5-chloro-2-(2-(3-chloro-4-methylphenyl)sulfonyl|iamino)ethyl)-1H-indol-3-yl|Ipropyl)benzoic acid

Stage 1: Methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)ubenzoate is added

3-Chloro-4-methylbenzenesulfonyl chloride by the procedure of Example 1, step 7, obtaining the product with a yield of 9895. "H NMR (400 MHz, SOCIi) 5 md. 1.95 (m, 2H), 2.40 (s, ЗН), 2 ... . 1H), 6.82 (s, 1H), 7.02 (m, 4H), 7.26 (m, 9H), 7.38 (dd, 9U-7.96, 1.89H, 1H), 7 .40 (d, and U-2.02Hz, 1H), 7.66 (d, 9U-1.77Hz, 1H), 7.96 (d, U-8.34Hz, 2H). "» Stage 2: The intermediate compound, which is an ester, is hydrolyzed in accordance with step 8 of example 1, obtaining after flash chromatography the acid indicated in the title with a yield of 4095. "H NMR (400 MHz, COS) 6 ppm 1.96 (m, 2H), 2.40 (s, ЗН), 2.73 (m, 4H), 2.83 (m, 2H), 2.98 (t, U-7.33Hz, 2H), 4.33 (t, 9U6.32Hz, 1H), 6.49 (d, U-8.84Hz, 1H), 6.80 (dd, U-8.84, 2.27Hz, 1H), 6.83 (s, 1H), 7.02 (m, 4H), 7.21 -1 (d, 9U-7.83HZ, 1H), 7.29 (m, 8H), 7.39 (m, 2H), 7.66 (d, 9U-1.77Hz, 1H), 8.00 (d, 9-8.08Hz , 2H). MS of high resolution calculations. for C 40Na6SiO/M»O,5 710.1773, found (ERIzh) 711.18411. E. anal. calculation for S.oNzeSioMoO,: C, 67.51; H, 5.10; M, 3.94. Found: C, 67.67; H, 5.27; M, 3.81. -1 50 Example 262: 4-2-P1-benzhydryl-5-chloro-2-(2-1(3-chloro-5-fluoro-2-methylphenyl)sulfonylamino)ethyl)-1H-indol-3-yl |iethoxy)benzoic acid

Co) Stage 1: This compound is prepared from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate and

3-chloro-5-fluoro-2-methylbenzenesulfonyl chloride by the procedure of example 1, stage 7 with a yield of 10095. "H NMR 22 (400 MHz, SOC) 5 mod. 2.26 (s, ЗН), 2.99 (m, 2Н) , 3.10 (m, 2H), 3.18 (t, 9-6.57Hz, 2H), 3.88 (s, ЗН), 4.21

HF) (t, 9-6.57Hz, 2H), 4.71 (t, 9-6.32Hz, 1H), 6.52 (d, 9U-8.84Hz, 71H), 6.81 (m, ЗН), 6.88 (s, 1Н), 7.04 (m, 4Н), 7.14 (d, 9-9.60 Hz, 1Н), 7.29 (m, 6Н), 7.52 (d , 9-2.02Hz, 1H), 7.58 (d, U-7.58Hz, 1H), 7.94 (m, 2H). di Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 6995. "H NMR (400MHz, SOCI") 5 ppm 2.26 (s ) . .04 (m, 4H), 7.15 (d, U-9.60Hz, 1), 7.29 (m, 6H), 7.52 (d, 9-2.02Hz, 1), 7.59 (d, 9U-7.58Hz, 1H), 7.99 (d, 9U-8.84Hz, 2H). High resolution MS calculated for

SzeNazzSi Mov 730,1471, found (ERICH) 731,1532.

Example 263: bo 4-(3-P1-benzhydryl-5-chloro-2-(2-1(3-chloro-5-fluoro-2-methylphenyl)sulfonyl|amino)ethyl)-1H-indol-3-yl |Ipropyl)benzoin on acid

Stage 1: Methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)ubenzoate is added

3-Chloro-5-fluoro-2-methylbenzenesulfonyl chloride by the procedure of Example 1, step 7, obtaining the product with a yield of 7595. "IN NMR (400 MHz, SOCI3) 5 ppm 1.95 (m, 2H), 2.27 ( s, ZN), 2.72 (sq., 9-7.58Hz, 4H), 2.89 (t, 9U-6.82Hz, 2H), 2.97 (m, 2H), 3.91 (s , ZN), 4.59 (t, 9U-6.19Hz, 1), 6.47 (d, 9-8.84Hz, 71H), 6.80 (dd, 9U-8.97, 2.y15Hz, 1H), 6.82 (s, 1H), 7.03 (dd, 9U-6.82, 2.53Hz, 4H), 7.13 (d, 9U-9.60Hz, 1), 7.24 ( d, 9-8.34Hz, 2H), 7.29 (m, 6H), 7.40 (d, 9-2.02Hz, 1H) 7.58 (d, 9U-7.58Hz, 1H), 7 .96 (d, U-8.34Hz, 2H).

Step 2: The intermediate, which is an ester, is hydrolyzed according to step 8 70. of example 1, obtaining the acid indicated in the title with a yield of 9695. "H NMR (400 MHz, SOCIv) 5 ppm 1.96 (m , 2H), 2.28 (s, ЗН), 2.74 (m, 4H), 2.89 (m, 2H), 2.99 (m, 2H), 4.65 (sq., U-6 ,32Hz, 1H), 6.47 (d, U-8.84Hz, 1H), 6.80 (dd, 9U-8.97, 2.15Hz, 1H), 6.82 (s, 1H), 7 .03 (m, 4H), 7.14 (d, 9-9.60Hz, 1H), 7.30 (m, 8H), 7.40 (d, 9-2.02Hz, 71), 7.58 (d, U-7.58Hz, 1H), 8.01 (d, U-8.08Hz, 2H). High resolution MS calculated for

СаоНз5СИЕМ2О,5 728.1679, found (ERI) 729.17441. E. anal. calculation for C.0NzvSiEM.O.5: C, 65.84; H, 75 4.83; M, 3.84. Found: C, 65.49; H, 5.02; M, 3.72.

Example 264: 4-(3-P1-benzhydryl-5-chloro-2-(2-N(2-nitrophenyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Ipropyl)benzoic acid

Stage 1: To methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6, example 1) is added 2-nitrobenzenesulfonyl chloride by the procedure of the example 1, stage 7, yielding product 7495. "H NMR (400MHz, SOCI3) 5 ppm 1.97 (m, 2H), 2.73 (sq., U-8.08Hz, 4H), 2 ... ... 4H), 7.24 (d, 9U-8.34HZ, 2H), 7.29 (m, 6H), 7.39 (d, 9U-2.02HZ, 1H), 7.50 (td, 9ET, 71, 1.26Hz, 1H), 7.65 (td, 9U-7.77, 1.39Hz, 1H), 7.75 (dd, U-7.83, 1.26Hz, 1H), 7.80 (dd, 9U-7.96, 1.14Hz, 1H), 7.96 (d, U-8.08Hz, 2H).

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 (Ge) of example 1, obtaining the acid indicated in the title with a yield of 10095. "H NMR (400 MHz, SOCI3) 5 ppm 1.98 (m , 2H), 2.75 (m, 4H), 2.92 (m, 2H), 3.06 (m, 2H), 5.35 (t, 9U-6.06HZ, 1H), 6.52 ( d, U-8.84Hz, 1H), 6.81 (dd, 8.84, 2.02Hz, 1), 6.91 (s, 1H), 7.07 (dd, 9U-6.82, 2 ... 7.76 (dd, 9U-7.83, 1.26Hz, 1H), 7.81 (dd, 9U-7.96, 1.14Hz, 1H), 8.01 (d, uU-8.34Hz, 2H).

High-resolution computing. for SzoNzaSIMzOv6Z 707.18568, found (ERY) 708.19296. -

Example 265: 4-2-11-benzhydryl-5-chloro-2-(2-X(2-nitrophenyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)" benzoic acid

Stage 1: This compound is prepared from Kk) methyl - 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate and 2-nitrosulfonyl chloride by the procedure of example 1, stage 7 with an output of 6390. IN nNMR (400 MHz, SOSI") 5 ppm 2.99 (m, 2H), 3.19 (m, 4H), 3.88 (s, ЗН), 4, 21 (t, 9-6.57Hz, 2H), 5.40 (t, 9U-6.19Hz, 1H), 6.57 (d, 9U-8.84Hz, 1H), 6.82 (m, ЗН ), 6.96 (s, 1H), 7.08 (m, 4H), 7.29 (m, 6H), 7.49 (td, 9U-7.71, 1.26HZ, 1H), 7, 52 (d, 9-1.77Hz, 1H), 7.65 (td, 9U-7.71, 1.26Hz, 1), 7.80 (m, 2H), 7.93 (d, 2H). "

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 from c of example 1, obtaining the acid indicated in the title with a yield of 90965. "H NMR (400 MHz, SOCIv) 5 ppm 2.99 (m , ts 2H), 3.20 (m, 4H), 4.23 (t, 9U-6.57Hz, 2H), 5.40 (t, 9U-6.19Hz, 1), 6.57 (d, U-8.84Hz, 1H), 6.84 (m, ZN), 6.95 "» (c, 1), 7.08 (m, uU-5.68, 3.66Hz, 4H), 7, 29 (m, 6H), 7.50 (m, 2H), 7.65 (td, 9U-7.77, 1.39HZ, MN), 7.80 (m, 2H), 7.98 (d, 2H). MS of high resolution calculations. for SzvNazoSIM53075 709.16495, found (ERY) 710.17059.

Example 266: 4-(2-(1-benzhydryl-5-chloro-2--2-Imesitylsulfonyl)amino|Iethyl)-1H-indol-3-yl)ethoxy| benzoic - I acid

Stage 1: This compound is obtained from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate and 2-mesitylenesulfonyl chloride

Sg" by the procedure of example 1, stage 7 with an output of 8995. H NMR (400 MHz, SOSI 3) 65 ppm. 2.24 (s, ZN), 2.48 (s, 6H), -1 50 2.90 (m, 2H), 3.05 (m, 2H), 3.16 (t, U-6.69Hz , 2H), 3.89 (s, ЗН), 4.17 (t, U-6.69Hz, 2H), 4.48 (t, U-644Hzc, 1H), 6.52 (d, U-8 , 84Hz, 1H). that) Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 6895. "H NMR (400 MHz, SOCI"z) 5 ppm 2.24 (with,

ЗН), 2.48 (s, 6H), 2.90 (sq., U-6.99Hz, 2H), 3.06 (m, 2H), 3.17 (t, 9U-6.69Hz, 2H ), 4.19 (t, 9U-6.57Hz, 2H), 22 4.BO (s, 1H), 6.52 (d, 9-8.84Hz, 1), 6.82 (m, 6H) , 7.02 (m, 4H), 7.29 (m, 6H), 7.52 (d, 9U-2.02Hz, 1H), 7.98

F! (d, --8.84Hz, 2H). MS of high resolution calculations. for S/4NzoSIMoOvBO 706.22682, found (ERIKHK) 70723370.

Example 267: o 4-(3-71-benzhydryl-5-chloro-2-(2-(2,4,6-trimethylbenzenesulfonylamino)ethyl-1H-indol-3-yl)ipropyl)benzoic acid 60 Stage 1: To methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6, example 1) add 2-mesitylenebenzenesulfonyl chloride by the procedure of example 1, stage 7 , obtaining the product with a yield of 8395. "H NMR (400 MHz, SNHOKOE SOSI3) 5 ppm 1.93 (m, 2H), 2.26 (s, ЗН), 2.47 (s, 6H), 2, 70 (m, 4H), 2.82 (m, 2H), 2.91 (m, 2H), 3.91 (s, ЗН), 4.36 (t, 9U-6.44ХС, 1H), 6 .46 (d, U-8.84Hz, 1H), 6.75 (s, 1H), 6.79 (dd, U-8.84, 227Hz, 1), 6.88 (s, 2H), 7 ,00 (m, 4H), 7.22 (d, 9U-8.34Hz, 2H), 7.28 (m, 6H), 7.39 (d, 62 )-2.02Hz, 1H), 7, 95 (d, U-8.34Hz, 2H).

Step 2: The intermediate, which is an ester, is hydrolyzed according to step 8 of example 1, obtaining the acid indicated in the title with a yield of 8495. "H NMR (400 MHz, SOCIv) 5 ppm 1.94 (m, 2H ), 2.26 (c, ЗН), 2.47 (c, 6Н), 2.71 (m, 4Н), 2.83 (m, 2Н), 2.93 (m, 2Н), 4.45 (t, 9-5.81Hz, 1H), 6.46 (d, уБ8В8аАГгЦц, 1H), 6.75 (s, 1H), 6.79 (dd, U-8.97, 2.15Hz, 71H) , 6.68 (s, 2H), 7.00 (m, 4H), 7.27 (m, 8H), 7.40 (d, 9U-2.02HZ, 1H), 8.01 (d, 9 -8.34Hz, 2H).MS of high resolution calculated for C 42НА4СИМ»О, 704.24756, found (ERI) 705.25452.

Example 268: 4-(3-1-benzhydryl-5-chloro-2-(2-(12-fluoro-6-«(trifluoromethyl)phenyl|sulfonyl)iamino)ethyl|-1H-indol-3-ylpropyl)benz 70 oleic acid

Stage 1: 2-Bromo-1-fluoro-3-fluoromethylbenzene (1.0 eq.) is added to a mixture of tetrahydrofuran (0.5M) and diethyl ether (0.5M) and cooled to -782C. n-butyllithium (2.5M, 1.Eq.) was added dropwise and the reaction mixture was stirred for 40 min. A volume of sulfur dioxide equal to the volume of THF is condensed and diluted with two volumes of ether. Using a cannula, the lithium salt of benzene is introduced into sulfur dioxide and the reaction mixture 75 is allowed to slowly warm to room temperature. The solvent is removed and the resulting salt is washed with ether, then transferred to hexanes (1.0M) and cooled in an ice bath. Sulfuryl chloride (1.0 beq.) was added, the reaction mixture was heated to room temperature and stirred for 5 hours. The solvent is removed, obtaining 2-fluoro-b-trifluoromethylbenzenesulfonyl chloride as a solid oily white substance with a yield of 6595. The product is used crude. "H NMR (400 MHz, DMSO-Ov) 5 ppm 7.46 (m, 1H), 7.52 (m, 2H).

Stage 2. 2-Fluoro-6-trifluoromethylbenzenesulfonyl chloride is added to methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|Ipropyl)benzoate by the procedure of example 1, stage 7, obtaining the product with a yield of 6295. "H NMR (400MHz, SOCI3) 5 ppm 1.94 (m, 2H), 2.73 (m, 4H), 2.91 (m, 2H), 2, 99 (m, 2H), 3.91 (s, ЗН), 4.87 (t, 9U5.81Hz, 1H), 6.50 (d, 9U-8.84Hz, 1H), 6.81 (dd, 9U-8.97, 215Hz, 2H), 7.03 (m, 4H), 7.24 s (d, --8.34Hz, 2H), 7.30 (m, 7H), 7.41 (d , U-2.02Hz, 1H), 7.62 (m, 2H), 7.95 (d, U-8.34Hz, 2H). He)

Step 3: The ester intermediate is hydrolyzed according to step 8 of example 1 to give the title acid in a yield of 5695. "H NMR (400MHz, SOCIv) 5 ppm 1.96 (m, 2H ), 2.75 (m, 4H), 2.92 (m, 2H), 3.00 (m, 2H), 4.93 (t, 9U-5.94Hz, 1H), 6.51 (d, U-8.84Hzc, 1H), 6.82 (m, 2H), sch 7.03 (m, 4H), 7.28 (m, 8H), 7.32 (d, 9U-1061Hzc, 1), 7.41 (d, 9U-2.02HZ, 1 H, ) 7.63 (m, 2H), 8.01 (d,

U-8.08Hz, 2H). MS of high resolution calculations. for (SloNzzSig;M2O,5'ANI 749.18585, found 749.18578. -

Example 269: "4-(2-711-benzhydryl-5-chloro-2-(2-(12-fluoro-6-trifluoromethyl)phenyl|sulfonylamino)ethyl|-1H-indol-3-yl)ethoxy)benzoin acid -

Stage |: 2-fluoro-6-trifluoromethylbenzenesulfonyl chloride is added to methyl o 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|vgthoxy)benzoate by the procedure of example 1, stage 7, obtaining a product with a yield of 8995. "YAN NMR (400MHz, SOCI3) 5 ppm 3.00 (m, 2H), 3.12 (m, 2H), 3.20 (t, U -6.44 Hz, 2H), 3.88 (s,

ZN), 4.20 (t, 9-644Hz, 2H), 4.99 (t, 9U-6.06Hz, 1H), 6.54 (d, uU-8.84Hz, 1H), 6.79 ( d, U-8.84Hz, 2H), 6.84 (dd, --8.97, 2.15Hz, 1H), 6.88 (s, 1H), 7.04 (dd, 9U-6.82 , 2.53Hz, 4H), 7.28 (m, 6H), 7.33 (m, 1H), 7.54 (d, « 40. 9-2.02Hz, 1H), 7.60 (m, 2H), 7.93 (d, U-9.10Gu, 2H). 8s Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8c of Example 1, obtaining the acid indicated in the title with a yield of 36965. "H NMR (400 MHz, SOSI") 5 ppm 3.01 (m, is" 2H), 3.13 (m, 2H), 3.21 (t, 9U-644Hz, 2H), 4.22 (t, 9-6.44Hz, 2H), 5.07 (t , 9U-6.06Hz, 1H), 6.55 (d, U-8.84Hz, 1H), 6.83 (m, ЗН), 6.88 (s, 1H), 7.04 (m, 4H ), 7.28 (m, 6H), 7.32 (m, 1H), 7.55 (d, 9U-2.02HZ, 1H), 7.61 (m, 2H), 7.98 (d, U-8.84Hz, 2H). High-resolution MS calculated for IS with 9NziSiRAM2O, ZANI 751.16511, found - and 751.16431. - Example 270: 4-(3-P1-benzhydryl-5-chloro-2-( 2-I(2,6-dimethylphenyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Ipropyl)benzoic acid t» Stage 1: 2,6-Dimethylbenzenesulfonyl chloride is obtained from 2-bromo-1,3-dimethylbenzene by procedure -I 50 of example 18, stages 1-2. The reaction gives the product in the form of a solid white substance with a yield of 8496. "H-NMR (400 MHz,

DMSO-O 5) 5 mg. 2.54 (s, 6H), 6.94 (d, 9U-7.33 Hz, 2H), 7.02 (m, 1H). d» Stage 2: 2,6-dimethylbenzenesulfonyl chloride is added to methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)ubenzoate by the procedure of example 1, stage 7, obtaining a product with a yield of 6696. "N

NMR (400 MHz, SOSI5) 5 ppm 1.93 (m, 2H), 2.50 (s, 6H), 2.70 (m, 4H), 2.82 (m, 2H), 2.93 (m, 2H), 3.91 (s , 59 ZN), 4.40 (t, 9U-6.32Hz, 1H), 6.47 (d, U-8.84Hz, 1H), 6.77 (s, 1), 6.80 (dd, U-8.97, 2.15 Hz, 1H), 7.00 (m,

HF) AN), 7.07 (d, 9-7.58 Hz, 2H), 7.22 (d, U-8.08 Hz, 2H), 7.27 (m, 7H), 7.40 (d, 9-2.02Hz, 1H), 7.95 (d, U-8.08Hz, 2H). t Stage 3: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 96965. "H NMR (400 MHz, DMSO-Ob) 5 ppm 1.81 vo (m, 2H,) 2.50 (s, 6H), 2.65 (m, 4H), 2.81 (m, 2H), 2.87 (m, 2H), 645 (d, 2-8, 84Hz, 1H), 6.77 (dd, 9U-8.84, 2.27Hz, 1H), 6.94 (s, 1H), 7.02 (m, 4H), 7.17 (d, 9U- 7.58HzC, 2H), 7.28 (d, uU-8.34HzC, 2H), 7.33 (m, 6H), 7.43 (d, 9U-2.27Hz, 1), 7.70 ( t, 9U-5.81Hz, 7), 7.85 (d, U-8.08Hz, 28). High resolution MS calculated for

ISliNzeSIM2O, ANI 691.23919, found 691.23872.

Example 271: 65 4-22-P1-benzhydryl-5-chloro-2-(2-S((2,6-dimethylphenyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid

Stage 1: Add to methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|htoxy)benzoate

2,6-dimethylbenzenesulfonyl chloride (Example 266, step 1) by the procedure of Example 1, step 7, obtaining the product with a yield of 88905. "H NMR (400 MHz, SOS) 6 mod. 2.51 (s, 6H), 2.90 (m , 2H), 3.06 (m, 2H), 3.16 (t, 5-6.69Hz, 2H), 3.89 (s, ЗН), 4.17 (t, 9U-6.57Hz ), 4.50 (t, 9U-6.19Hz, 1H), 6.53 (d, 9U-8.84Hz, 1H), 6.79 (d, uBOlLOGHtz, 2H), 683 (m, 2H), 7.02 (m, 4H), 7.06 (d, 9-7.58Hz, 2H), 7.23 (m, 7H), 7.28 (m, 6H), 7.53 (d,

U-2.02Hz, 1H), 7.93 (d, U-8.84Hz, 2H).

Step 2: The ester intermediate is hydrolyzed according to step 8 of example 1 to give the title acid in a yield of 79965. "H NMR (400MHz, DMSO-O7) 5 ppm 2.48 (s , 6H), 2.85 (m, 2H), 2.95 (m, 2H), 3.08 (t, 9U-6.57Hz, 2H), 4.15 (t, U-6.69Hz, 2H ), 6.48 (d, U-8.84Hz, 1H), 70 6.79 (dd, 9U-8.84, 1.77Hz, 1H), 6.90 (d, 9U-8.84Hz, 2H ), 6.95 (s, 1H), 7.01 (m, 4H), 7.14 (d, 9U-7.58Hz, 2H), 7.29 (m, 6H), 7.63 (d, U-2.02Hz, 1), 7.73 (t, 9U-5.94Hz, 1H), 7.82 (d, 9U-8.84Hz, 2H). High resolution MS calculation for (C4o0NaU SIM2OB5Z'ANI 693.21845, found 693.21791.

Example 272: 4-2-(1-benzhydryl-5-chloro-2-(2-1(2,6-diethylphenyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy) benzoic acid

Stage 1: 2,6-Diethylbenzenesulfonyl chloride is obtained from 2-bromo-1,3-diethylbenzene by the procedure of example 18, stages 1-2. The reaction gives the product in the form of a solid oily pale yellow substance with a yield of 3695. TN-NMR (400 MHz, DMSO-O5) 5 ppm. 1.13 (t, U-7.33Hz, 6H), 3.08 (sq., U-7.33Hz, 4H), 6.96 (d, U-7.58Hz, 2H), 7.10 ( m, 1H).

Stage 2: To methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|htoxy)benzoate is added 2,6-diethylbenzenesulfonyl chloride by the procedure of example 1, stage 7, obtaining the product with a yield of 7295. "H 70 nNMR (400 Hz4, DMSO-O6) 5 ppm 1.10 (t, 9U-7.33Hz, 6H), 2.91 (m, 6H), 2.99 (m, 2H), 3.11 (t, U-6.69Hz, 2H), 3.81 (s, ЗН), 4.18 (t, 9U-669Hz, 2H), 6.49 (d, 9U -8.84Hz, 1), 6.80 (dd, 9U-8.84, 2.02Hz, 7H), 6.93 (d, -8.84Hz, 2H), 6.97 (s, 1H), 7.02 (m, 4H), 7.17 (d, 9U-7.58Hz, 2H), 7.32 (m, 5H), 7.38 (t, 9U-7.71Hz, 1H), 7, 65 (d, 9-2.02 Hz, 1), 7.74 (6 9-5.94 Hz, 1H), 7.85 (d, U-8.84 Hz, 2H). is a complex ester, hydrolyzed in accordance with stage 8 of example 1, obtaining the acid specified in the title with a yield of 8895. "H NMR (400MHz, DMSO-Ov) 5 ppm 1.10 (8) (t, 9U-7.33Hz, 6H), 2.91 (m, 6H), 2.98 (d, 9U-7.83Hz, 2H), 3.10 (t, 9- 6.57Hz, 2H), 4.17 (t, U-6.69Hz, 2H), 6.49 (d, U-8.84Hz, 1H), 6.80 (dd, U-8.84, 2 ,02Hz, 1), 6.91 (d, 9U-9.09Hz, 2H), 6.97 (s, 1H), 7.02 (m, 4H), 7.17 (d, 9-7.58Hz , 2H), 7.32 (m, 5H), 7.38 (t, U-7.58Hz, 1H), 7.65 (d, uU-2.27Hz, 1H), 7.74 (t, 9U -5.81Hz, 1H), 783 suzo (d, --8.84Hz, 2H). MS of high resolution calculations. for |Sl2NA«SIM2OB5Z'ANI 721.24975, found 721.24876.

Example 273: - 4-(3-P1-benzhydryl-5-chloro-2-(2-C(2,6-diethylphenyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Ipropyl)y benzoic acid "Mr

Stage 1: To methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)ubenzoate is added 2,6-diethylbenzenesulfonyl chloride (Example 268, stage 1 ) by the procedure of example 1, stage 7, obtaining the product - z with yield 7195. "H NMR (400 MHz, DMSO-Ov) 5 ppm 1.11 (t, 9-7.33 Hz, VN), 1.81 ( m, 2H), 2.65 (m, 4H), 2.84 (m, 2H), 2.90 (m, 6H), 3.84 (s, ЗН), 6.44 (d, 2-8 ,84Hz, 1H), 6.77 (dd, U-8.84, 2.02Hz, 1H), 6.94 (s, 1H), 7.02 (m, 4H), 7.19 (d, 9U -7.58Hz, 2H), 7.33 (m, 7H), 7.40 (t, 9-7.71Hz, 1H), 7.43 (d, 9U-2.02Hz, 1), 7.70 (t, 4-5.68Hz, 1H), 7.86 (d, U-8.34Hz, 2H).

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 8595. "H NMR (400MHz, DMSO-O6) 5 ppm 1.11 - s (t, 9U-7.33HZ, 6H), 1.81 (m, 2H), 2.65 (m, 4H), 2.84 (m, 2H), 2.91 (m, 6H), 6, 45 (d, U-8.84Hz, 1H), 6.77 (dd, "» 3-8.84, 2.02Hz, 1H), 6.95 (s, 1), 7.02 (m, 4H ), 7.19 (d, 9U-7.58Hz, 2H), 7.28 (d, U-8.34Hz, 2H), 7.33 (m, " 5H), 7.40 (m, 1) , 7.43 (d, 9-2.27Hz, 1H), 7.70 (t, 9U-5.68Hz, 1), 7.84 (d, U-8.34Hz, 2H). . for |C4zNazSIM2O,5'ANI 719.27049, found 719.27028.

Example 274: - 4-2-P1-benzhydryl-5-chloro-2-(2-(2,6-dimethoxyphenyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy) benzoic acid

Step 1: 1,3-Dimethoxybenzene (1.0 eq.) is placed in diethyl ether (0.2 M) and n-butyllithium (1.0 eq.) is added dropwise. The reaction mixture is refluxed for three hours. The mixture -I 20 is cooled to room temperature, then it is placed in a bath made of a mixture of dry ice and acetone and cooled to -502С7. Bromide (0.98 eq.) was added and the reaction mixture was allowed to slowly warm to room temperature. The reaction mixture is quenched with a saturated solution of sodium thiosulfate and the aqueous layer is extracted with ether.

The organic extracts are washed with saturated salt solution, dried over sodium sulfate and concentrated to give a brown solid. The solid was recrystallized from hexane to give product 29 as a white solid with a yield of 2795. IN NMR (400MHz, DMSO-O5) 5 ppm. 3.83 (c, 6H), 6.73

HF) (d, U-8.34Hz, 2H), 7.30 (t, U-8.34Hz, 1H). t Stage 2: 2,6-Dimethoxybenzenesulfonyl chloride is prepared from 2-bromo-1,3-dimethoxybenzene by the procedure of Example 1, Stage 1. The reaction gives a mixture of sulfonyl chloride and another product as a white solid.

Stage 3: 2,6-dimethoxybenzenesulfonyl chloride is added to methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|htoxy)benzoate by the procedure of example 1, stage 7 , giving a product with an output of -7295. "IN NMR (400MHz, SOSIv) 5 ppm 3.08 (m, 2H), 3.14 (m, 2H), 3.20 (t, 9-6.69Hz, 2H), 3.64 ( s, 6H), 3.88 (s, ЗН), 4.18 (t, U-6.69Hz, 2H), 5.41 (t, 9U-5.68Hz, 1H), 6.42 (d, 9U-8.84Hz, 1H), 6.52 (d, U-8.59Hz, 2H), 6.79 (m, ЗН), 6.91 (s, 1H), 7.02 (m, 4H) , 7.25 (m, 6H), 7.36 (t, 9U-8.46Hz, 1H), 7.54 (d, 9U-2.02Hz, 1H), 7.93 (d, be -8 84Hz, 2H), t/2 (M-) 737.

Step 4: The intermediate, which is an ester, is hydrolyzed according to step 8 of example 1 to give the title acid in a yield of 10095. "H NMR (400 MHz, SOCl3) 5 ppm 3.08 (m, 2H ), 3.15 (m, 2H), 3.21 (t, U-6.69Hz, 2H), 3.64 (s, 6H), 4.20 (t, 9U-6.57Hz, 2H), 5.44 (m, 1H), 6.42 (d, u8.84Hz, 1), 6.53 (d, 9U-8.59Hz, 2H), 6.79 (dd, uU-8.84, 2 ,02Hz, 1H), 6.83 (d, U-8.84Hz, 2H), 6.91 (s, 1H), 57.02 (m, 4H), 7.25 (m, 6H), 7, 36 (t, U-8.46Hz, 1H), 7.54 (d, 9U-2.02Hz, 1H), 7.98 (d, 9U-8.84Hz, 2H). High resolution MO calculated for | SaoNaUSIM2O7Z'ANI 725.20729, found 719.27028.

Example 275: 4-(3-P1-benzhydryl-5-chloro-2-(2-((2,6-dimethoxyphenyl)sulfonyl|aminoethyl)-1H-indol-3-yl|Ipropyl)benzoic acid 70 Stage 1: To methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate is added 2,6-dimethoxybenzenesulfonyl chloride (example 270, stage 1) by the procedure of example 1 , stage 7, yielding product 80905. TN-NMR (400MHz, SOSI") 5 ppm IN NMR (400MHz, SOSI") 5 ppm 1.94 (m, 2H), 2.72 ( m, 4H), 3.01 (m, 4H), 3.59 (s, 6H), 3.91 (s, ЗН), 5.37 (m, 1H), 6.37 (d, 9U-8 ,84Hz, 1H), 6.53 (d, U-8.59Hz, 2H), 6.76 (dd, 9U-8.97, 2.15Hz, 1H), 6.84 (s, 1H), 6 .98 (m, 4H), 7.21 (d, U-8.34Hz, 2H), 7.26 (m, 6H), 7.38 (m, 15. 2H), 7.94 (d, U -8.34Hz, 2H), t/2 (Mk) 737.

Step 2: The ester intermediate is hydrolyzed according to step 8 of example 1 to give the title acid in a yield of 9195. "H NMR (400 MHz, SOCIv) 5 ppm 1.95 (m, 2H ), 2.74 (m, 4H), 3.02 (m, 4H), 3.60 (s, EN), 5.41 (s, 1H), 6.37 (d, 9U-8.84HZ, 1H), 6.53 (d, U-8.59Hz, 2H), 6.76 (dd, U-8.84, 2.27Hz, 1H), 6.84 (s, 1H), 6.99 ( m, 4H), 7.25 (m, 8H), 7.37 (t, 9U-8.46GuC, 1), 7.40 (d,

U-2.02Hz, 1), 7.99 (d, U-8.34Hz, 2H). MS of high resolution calculations. for IS 54NzoSIMOOvZaNiI 723.22902, found 723.22893.

Example 276: 4-2-(/1-benzhydryl-5-nitro-2-(3-phenylmethanesulfonylpropyl)-1H-indol-3-yl|ethoxy) benzoic acid

Step 1: 4-Nitroaniline (1.0 eq.) is added to a mixture of water (0.8M) and concentrated HCl (10.8M). Iodine monochloride (Teq.) is added to a mixture of 4:1 with 29 of water and concentrated HCl (1.3M) and cooled to 02C. ISI solution is added to the aniline solution and the reaction mixture is left at room temperature for 20 hours. The reaction mixture was filtered to give the iodinated product as a yellow solid with a yield of 97.395. "NN NMR (ZO00MHz, DMSO-Ov) 6 ppm 6.75 (d, 9U-9.07Hz, 1H), 7.98 (dd, 9U-9.07, 2.47Hz, 1H), 8 ,40 (d, 9-2.47Hz, 1H), M5 sch 30 t/2 263 (M-H).

Step 2. 2-Iodo-4-nitroaniline (Eq.) and benzhydryl bromide (1.3 eq.) are added to dichloroethane (0.8M). Add to diisopropylethylamine (1.1 eq.) and the reaction mixture is heated at 502C for 20 hours. The reaction mixture is cooled and washed with other aqueous solution, dried with Ma»5O, and concentrated. Purification using flash chromatography (1095 ethyl acetate in hexanes) gave the alkylated product in 8195 yield. "H NMR (400MHz, in 35SOCI3) 5 mod. 5.56 (d, 4-4.80Hz, 1H), 5.67 (d, 9U-5.05Hz, 1H), 6.36 (d, U-910Hz, 1H), 7.32 (m, 6H), 7.58 (m, p

AN), 7.99 (dd, U-9.09, 2.53Hz, 1H) 8.61 (d, 9U-2.53Hz, 1H).

Stage 3. Benzhydryl-(4-nitro-2-iodophenyl)amine (Tekv.), methyl ester of 4-(6b-hydroxyhex-3-ynyloxy) benzoic acid is added to a round-bottomed flask containing 10 ml of DMF that has been degassed with argon " (1.Eq.), ISI (Teq.), COAc (5 eq.) and palladium(II) acetate (0.04 eq.). The reaction mixture is heated at 10022 for 40.7.5 hours. Then it is cooled, diluted with ethyl acetate, washed with water and a saturated salt solution, dried over Na2O, and concentrated to obtain a solid brown substance. Purification by flash chromatography a affords two products, 4-2-I(/1-benzhydryl-5-nitro-2-(2-hydroxyethyl)-1H-indol-3-yl|Hiethoxy)benzoic acid methyl ester and the desired 4-2-(1-Benzhydryl-5-nitro-3-(2-hydroxyethyl)-1H-indol-2-yl|ethoxy)benzoic acid methyl ester in total yield 7195. The products cannot be separated by flash chromatography and both 45 are used at the next stage. IN NMR (400MHz, SOSIz) 5 ppm 1.66 (t, 9U-5.56Hz, 1H), 1.80 (t, - 35-5.18Hz, 7), 3, 14 (m, 4H), 3.35 (m, 4H), 3.81 (m, 2H), 3.87 (m, 9U-1.52Hz, 6H), 3.97 (sq., 9U-6 ,32Hz, 2H), -I 4.10 (t, 9U-6.82Hz, 2H), 4.31 (t, 9U-619Hz, 2H), 6.58 (d, 9U-4.04Hz, 1) , 6.60 (d, 9-4.04Hz, 1H), 6.67 (d, 5-9 10Hz, 2H), 6.89 (d, 9U-8.84Hz, 2H), 7.10 (m , 9H), 7.20 (s, 1H), 7.32 (m, 12H), 7.75 (m, 2H), 7.90 (d.. pi -8.84Hz, 2H), 7.95 (d, 9U-9.09Hz, 2H), 8.52 (d, 92.27Hz, 1H), 8.59 (d, 9U-2.27Hz, 1H). -1 50 Stage 4. Regioisomers (1 .0 eq.) from the previous step is transferred to THF. Triethylamine (1.2 eq.) and methanesulfonylchloro are added reed (1.2 eq.). The reaction mixture is stirred until the starting substance is consumed, which o) is monitored by TLC. The reaction mixture is diluted with dichloromethane and washed with water and saturated salt solution. The mixture is dried over MA»bO), and concentrated. The reaction gives an indivisible mixture of isomers with a yield of 10095. "N

NMR (400 MHz, SOSIZ) 5 mod. 2.81 (s, ZN), 2.90 (s, ZN), 3.35 (m, 8H), 3.87 (m, 9U-1.52Hz, 6H), 4.07 (t,

U-6.19Hz, 2H), 4.14 (t, 9-7.20Hz, 2H), 4.30 (t, U-6.06Hz, 2H), 4.49 (t, 9U-669Hz, 2H ), 6.62 (d, 9-6.57 Hz,

HF) 1H), 6.65 (d, 9U-6.57Hz, 1H), 6.69 (d, U-8.84Hz, 2H), 6.88 (d, 9U-9.09Hz, 2H), 7.02 (s, 1H), 7.10 (dd, 9-7.71, 4.67 Hz, 8H), 7.23 (s, 1H), 7.34 (m, 12H), 7.79 ( m, 2H), 7.91 (d, 9U-8.84Hz, 2H), 7.96 (d, 9U-8.84Hz, 2H), 8.49 po (d, 9-2.27HzC, 1H) , 8.62 (d, U-2.02 Hz, 1H).

Stage 5. A mixture of crude mesylates from the previous stage (Eq.) and sodium azide (2.2 eq.) is transferred to 60 DMSO (0.05 M). The reaction mixture is stirred at room temperature until the disappearance of the starting substance that controls TLC. The reaction mixture is diluted with ethyl acetate, washed with water and saturated salt solution, dried over Na»80O), and concentrated, obtaining the desired azides in quantitative yield. "H NMR (400MHz, SOSI"v) 5 ppm 3.12 (m, 4H), 3.33 (m, 6H), 3.64 (t, 9U-6.82Hz, 2H), 3, 88 (m, 9U-1.52Hz, 6H), 4.05 (t, 9U-6.32Hz, 2H), 4.29 b (t, 9U-6.19Hz, 2H), 6.65 (m, 4H), 6.87 (d, U-8.84HZ, 2H), 7.02 (s, 1H), 7.10 (m, 8H), 7.21 (s, 1H), 7.34 (m , 12H), 7.78 (m, 2H), 7.91 (d, U-8.84Hz, 2H), 7.96 (d, U-8.84Hz, 2H), 8.49 (d, 9 -2.27 Hz, 1H), 8.61 (d, 9-2.27Hz, 1H).

Step 6. A mixture of undissociated azides (1.Eq.) from step 5 and triphenylphosphine (1.1Eq.) is taken up in THF and stirred at room temperature until the starting material disappears, yielding a product with a higher CI by TLC. One ml of water is added to the reaction mixture and it is continued to stir at room temperature until TLC shows the disappearance of the intermediate compound with a higher CI. The THF is removed in vacuo and the resulting solid is taken up in ethyl acetate, washed with water and saturated salt solution, dried over Na»5O, and concentrated. Purification by flash chromatography gave a total yield of recovered products equal to 43905. The regioisomers were separated using flash chromatography (gradient elution from 0.2595 methanol in dichloromethane to 1095 methanol in dichloromethane). Regioisomers identify 7/0 NMR and the desired compound, 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-nitro-1H-indol-3-yl|ethoxy)benzoic acid methyl ester, is selected for the next stage. "H NMR (400 MHz, SOSIz) 5 ppm 3.30 (m, 6H), 3.88 (s, ЗН), 4.27 (t, 9-6.57 Hz, 2H), 6, 56 (d, 9U-9.35Hz, 1H), 6.88 (d, U-910Hz, 2H), 7.10 (dd, U-6.44, 2.65Hz, 4H), 7.32 (m , 7H), 7.72 (dd, 9U-9.09, 2.27Hz, 1H), 7.95 (d, --8.84Hz, 2H), 8.60 (d, 9-2.27Hz, 1H). MS t/: 550 (Mu). 15 Stage 7: To 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-nitro-1H-indol-3-yl|Iethoxy) methyl ether of benzoic acid, "-toluenesulfonyl chloride is added by the procedure of Example 1, step 7, to give the product in yield 6196. .25 (t, U-6.06Hz, 2H), 3.88 (s, ЗН), 4.09 (s, 2H), 4.15 (m, 1H), 4.25 (t, U-6 ,06Hz, 2H), 6.61 (d, 9U-9.35Hz, 1H), 6.84 (d, 9U-8.84Hz, 2H), 6.97 (s, 1H), 7.07 (m , 4H),7.20 (m, uU-8.08, 1.52Hz, 2H), 7.32 (m, 9H), 7.77 (dd, U-9.10, 2.27Hz, 1H) , 7.95 (d, U-9/10Hz, 20 2 H), 8.59 (d, 9-52.27Hz, 1H). MS t/l: 703 (M-N).

Step 8: The ester intermediate is hydrolyzed according to step 8 of example 1 to give the title acid in a yield of 75965. "H NMR (400 MHz, SOCIv) 5 ppm 2.90 (m, 2H ), 3.10 (m, 2H), 3.26 (t, U-6.06Hz, 2H), 4.10 (s, 2H), 4.26 (t, U-6.06Hz, 2H), 4.37 (t, 9-6.19Hz, 1H), 6.61 (d, 9U-9.35Hz, 1H), 6.85 (d, U-9.09Hz, 2H), 6.97 (s , 1H), 7.07 (m, 4H), 7.20 (m, 2H), 7.32 (m, 9H), 7.76 (dd, s 25 9-9.10, 2.27Hz, 1H ), 7.97 (d, 9U-8.84 Hz, 2H), 8.58 (d, 9-2.27 Hz, 18). High-resolution MS calculated for He)

SzenzMaO7.5 689.2196, found (ERI) 690.22581.

Example 277: 4-2-11-benzhydryl-5-chloro-2-12-((42-(2-chloro-1-methylethyl)benzene)sulfonyl)amino|ethyl)-1H-indol-3-yl|propyl ) benzoic acid ch 30 Stage 1: To methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6, - example 42) add 2-(2-chloro-1-methylethyl)benzenesulfonyl chloride by the procedure of example 1, stage 1, obtaining a product with a yield of 6590. t

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 - example 1, obtaining the acid indicated in the title with a yield of 10095. MS high-resolution calculations. for

From ISloNaosSiM20.5' ANI 739.21586, found 739.21611. -

Example 278: 4-(2-(1-benzhydryl-2-2-((2-(2-chloro-1-methylethyl)benzene)amino|ethyl)-5-chloro-1H-indol-3-yl)ethoxy | benzoic acid «

Stage 1: This compound is obtained from methyl C7Z 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and c 2-(2-chloro-1-methylethyl)benzenesulfonyl chloride by the procedure of Example 1, step 7 to yield 61905. "c Step 2: The intermediate, which is an ester, is hydrolyzed according to step 8 of example 1 to give the title acid with a yield of 90905. t/2 (M-1)-739.3.

Example 279: 4-2-11-benzhydryl-5-chloro-2-(2-I((2,6-dimethylbenzyl)sulfonyl|amino)zetyl)-1H-indol-3-ilyethoxy)benzoic acid -I Stage 1: This compound is obtained from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and t 2 ,6-dimethylbenzylsulfonyl chloride by the procedure of example 1, stage 7 with a yield of 45905. -I 250 Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 88905. t/2 (M-1)-738.2. o Example 280: 4-I3-(1-benzhydryl-5-chloro-2-22-(cyclopropylsulfonyl)amino|ethyl)-1H-indol-3-yl)propyl|Isenzoine acid

Stage 1: This compound is prepared from methyl 99 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and

HF) of cyclopropanesulfonyl chloride by the procedure of example 1, stage 7 with a yield of 8395. t Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 8095. High resolution MS calc. for

Cz6Hz5CIM2O,5 626,2006, found (ERIk) 62720734. 60 Example 281: 4-13-(/1-benzhydryl-5-chloro-2-(2-1(2-phenylethyl)sulfonyl|amino)ethyl)-1H -indole-Z-yl|propyl) benzoic acid

Stage 1: To methyl 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoate (stage 6, example 42) add phenylethanesulfonyl chloride (obtained, respectively to the procedure U.Ogud.Spet. 1984, 49, 5124-5131) by the procedure of example 1, stage 7, obtaining a product with a yield of 7790. bo Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed according to stage 8 of example 1 , obtaining the title acid with a yield of 8295. High-resolution MS calcd. for

CA4NzoSIM2O,5 690.2313, found (ERI) 691.2383.

Example 282: 4-2-11-benzhydryl-5-chloro-2-(2-N(2-phenylethyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid

Stage 1: This compound is prepared from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and phenylethanesulfonyl chloride by the procedure of example 1, stage 7 with output 81 95.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 7/0 of example 1, obtaining the acid indicated in the title with a yield of 8575. MS high-resolution calculations. for

S.oNz7SIMoOvZ 692.2115, found (Erykh) 693.2185.

Example 283: 2-12-(/1-benzhydryl-5-chloro-2-(2-phenylmethanesulfonylaminoethyl)-1H-indol-3-yl|ethoxy) benzoic acid

Stage 1: Crude 2-11-benzhydryl-2-(2-(tert-butyldiphenylsilanyloxy)ethyl|-5-chloro-1H-indole-3-ylethanol 7/5 From stage 6 of example 143 is treated with methyl ester of 3-hydroxybenzoic acid by the procedure of example 143, step 8, obtaining the desired 3-(2-11-benzhydryl-2-(2-(tert-butyldiphenylsilanyloxy)ethyl|-5-chloro-1H-indol-3-ylethoxy)benzoic acid methyl ester. output 8595.

Step 2: The deprotected compound is prepared by the procedure described in Example 143, Step 9.

Crude methyl ester of 3-72-(1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl|Iethoxy)benzoic acid is directly used in the next stage without additional purification.

Stage 3-5: /3-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoic acid methyl ester is obtained by the procedure described in example 147, stage 3-7 with an output of 5795 (for the 3rd stage).

Stage 6: O-toluenesulfonyl chloride is added to the methyl ester of 3-12-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoic acid by the procedure of example 1, stage 7, obtaining a product with a yield of 7390. i9)

Stage 7: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 8895. MS high-resolution calculations. for

ІзеНз5СИМ2О5 АНИ 679.2028, found 679.2029. Ha

Example 284: 2-(2-7-1-benzhydryl-5-chloro-2-(2-(3,4-dichlorophenylmethane-sulfonylamino)ethyl/|-1H-indol-3-yl|ethoxy) benzoic acid "

Stage 1: 3,4 -dichlorophenylmethanesulfonyl chloride by the procedure of example 1, stage - 7, obtaining a product with a yield of 8490.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9195. MS high-resolution calculations. for

ISzeNzzSiIzM2O55'ANI 747.12486, found 747.12423.

Example 285: 3-2-|(1-benzhydryl-5-chloro-2-(2-phenylmethanesulfonylaminoethyl)-1H-indol-3-yl|Iethoxy)benzoin

Acid shshc Stage 1: Crude 2-11-benzhydryl-2-(2-(tert-butyldiphenylsilanyloxy)ethyl|-5-chloro-1H-indol-3-ylethanol and from stage 6, example 143 is treated with 2-hydroxybenzoic acid methyl ether acid by the procedure of Example 143, "" stage 8, obtaining the desired methyl ester 2-(2-711-benzhydryl-2-(2-(tert-butyldiphenylsilanyloxy)ethyl|-5-chloro-1H-indol-3-yl)letoxy) of benzoic acid /-z

YIELDING 6095. -i Step 2: The deprotected compound is prepared by the procedure described in Example 143, Step 9.

Crude methyl ether of /2-12-(/1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl|ethoxy)benzoic acid is directly used in the next stage without additional purification. Stage 3-5: 2-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoic acid methyl ester

Acids are obtained by the procedure described in example 147, stages 3-7 with a yield of 6095 (from stage 3).

Che Stage 6: To 2-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoic acid methyl ester

HY6) acid is added with o-toluenesulfonyl chloride by the procedure of Example 1, step 7, to give a product with a yield of 9090.

Stage 7: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9095. MS high-resolution calculations. for o ISzenz5SIM2OBa ANI 679.2028, found 679.20358.

Example 286: co 3-(2-71-benzhydryl-5-chloro-2-(2-(3,4-dichlorophenylmethane-sulfonylamino)ethyl-1H-indol-3-yl)ethoxy)benzoic acid 60 Stage 1: To 2-12-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoic acid methyl ether (stage 5, example 281) add 3,4-dichlorophenylmethanesulfonyl chloride by the procedure of example 1, step 7, giving product with a yield of 84905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 8995. MS high-resolution calculations. for 65 ISZENZAZSIZMOOB'ANI 747.12486, found 747.12457.

Example 287: 4-(2-(1-benzhydryl-5-chloro-2-2-(((2,4-dichlorophenyl)

sulfanyl|methylisulfonyl)amino|ethyl)-1H-indole-3-yl)ethoxy|benzoic acid

Step 1: To methyl 4-2-(1-benzhydryl-5-chloro-2-(2-chloromethanesulfonylaminoethyl)-1H-indol-3-yl ethoxy)benzoate, Example 81, Step 1, is added 2,4-dichlorothiophenol by the procedure of Example 81, stage 2. The crude substance is purified by preparative HPLC with a yield of 50905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 100905. t/2 (M-1) 776.92.

Example 288: 4-(2-(1-benzhydryl-5-chloro-2-2-(((2,4-difluorophenyl)thio) 7/0 methyl)sulfonyl)amino|ethyl)-1H-indole-3- yl) ethoxy) benzoic acid

Step 1: To methyl 4-2-(1-benzhydryl-5-chloro-2-(2-chloromethanesulfonylaminoethyl)-1H-indol-3-yl ethoxy)benzoate, Example 81, Step 1, is added 2,4-difluorothiophenol by the procedure of Example 81, stage 2. The crude substance is purified by preparative HPLC with a yield of 2790.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 100905. t/2 (M-1) 744.97.

Example 289: 4-(2-(1-benzhydryl-5-chloro-2-2-(((3,4-dichlorophenyl)sulfinyl|methyl)isulfonyl)amino|ethyl)-1H-indol-3-yl)ethoxy Benzoic acid

Stage 1: Methyl 4-(2-(1-benzhydryl-5-chloro-2-12-I4(3,4-dichlorophenyl)thio|methyl)sulfonyl)amino|ethyl)-1H-indol-3-yl)ethoxy |benzoate (stage 1 of example 219) in THF oxidize moSRBA (1.1 equiv.). The crude substance is purified by flash column chromatography using a mixture of 3090 E(UAc/hexane with a yield of 42905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 93905. t/: (M-Y) 795.14. with

Example 290: 4-2-(1-benzhydryl-5-chloro-2-(2-C(2-hydroxyphenyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy) benzoic acid i)

Stage 1: Hydrogenate 4-(2-(1-benzhydryl-5-chloro-2-12-(2-(2-methylpenta-2,4-dienyloxy)benzenesulfonylamino|ethyl)-1H-indol-3-yl)ethoxy

Ibenzoic acid (0.55g, 0.7Omol) (stage 1, example 183) and 1095 Pa/C (55mg) in MeOnH (30ml) and EOH (20ml). The resulting mixture is filtered through celite and concentrated. The residue is subjected to chromatography using a mixture of 35-40956 E(OAc/hexane), obtaining the desired product (0.50 g, 95965). -

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 "g of example 1, obtaining the acid indicated in the title with a yield of 9095. MS high-resolution calculations. for

СзвНззСИМоО5 680.1748, found (ERY) 681.18118. -

Example 291: th-

M-2-P-benzhydryl-5-chloro-3-(2-14-I(2)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)umethyl|phenoxy)ethyl)-1H- Indole-2-ylethyl)-1-(3,4-dichlorophenyl)methanesulfonamide

Stage 1: 2-71-benzhydryl-2-(2-(tert-butyldiphenylsilanyloxy)ethyl|-5-chloro-1H-indol-3-yl)ethanol (stage 6, example 142) is combined with 4-hydroxybenzaldehyde at under the conditions described in example 189, stage 1, obtaining "4-(2-71-benzhydryl-2-(2-(tert-butyldiphenylsilanyloxy)ethyl|-5-chloro-1H-indol-3-yl)ethoxy)benzaldehyde with with output 7095. Stage 2: Deprotect the silyl ether from the previous stage, according to the procedure of example 143, and? step 9 to give 4-12-(1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl|ethoxy)benzaldehyde in 9090 yield.

Stage 3: The alcohol from the previous stage is activated by conversion to mesylate, as described in stage 10-I of example 143, obtaining the desired mesylate, which is used in the next stage without purification.

Step 4: The mesylate from the previous step is treated under the conditions described in step 11 of example 143,

Obtaining 4-(2-(2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-ilyethoxy)benzaldehyde with a yield of 98905 (for two stages).

Stage 5: A mixture of 4-2-(2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indole-3-yl|htoxy) benzaldehyde (1.29G, - 2.A1mmol, 1.Eq. ), 2,4-thiazolidinedione (0.41g, 3.1Zmmol, 1.Eq.) and piperidine (0.12ml, 1.21mmol,

He O,bBekw.) in EYN (125 ml) is boiled under reflux overnight. EN is removed under vacuum.

The residue is diluted with EAs and washed with water, then with a saturated salt solution. The organic layer is dried over

Ma5O, and concentrate, and the residue is chromatographed using a 30-3595 EtOAc/hexane mixture to give 5-(4-12-(2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indole-3 -yl|Iethoxy)benzylidene)thiazolidine-2,4-dione (1.33g, 8796).

F) Stage 6: RA 9P is added in small portions to a solution of the product from stage 5 in THF (80 ml). The mixture is stirred for 1 day. Add Zml of water and stir for an additional 2 days. The resulting solid was filtered off and identified by LC/MS as the triphenylphosphinimine of the above azide (6095). in Stage 7: The imine (25Omg, 0.29mmol, 1.Eq.) from stage 6 and (3,4-dichlorophenyl)methylsulfonyl chloride in a mixture of СНоСИ» (10 ml) and saturated MnSO» (ml) are stirred overnight by the procedure of example 1, stage 7, obtaining a product with a yield of 7905. t/2 (M-1) 830.45.

Example 292:

IM-(2-(1-benzhydryl-5-chloro-3-12-(4-(2,4-dioxothiazolidin-5-ylidenemethyl)phenoxy|ethyl)-1H-indol-2-yl|ethyl)-2- methyl 65 lbenzenesulfonamide

Stage 1: A mixture of triphenylphosphinimine (300mg, 0.5mmol, 1.Eq.) from stage b of Example 287 and

of 2-methylbenzenesulfonyl chloride in a mixture of CHClCl (15 ml) and saturated MnSO (5 ml) was stirred overnight by the procedure of example 1, stage 7, obtaining a product with a yield of 395. High-resolution MS calcd. for

ISl2NzvSIMzO5Z-NI 760.1723, found 760.1728.

Example 293: 4-(3-P1-benzhydryl-5-chloro-2-(2-X(1-methyl-1H-imidazol-2-yl)sulfonylamino)ethyl)-1H-indol-3-yl|Ipropyl) benzoic acid

Stage 1: 1-Methyl- 1H-imidazole-2-sulfonyl chloride by the procedure of Example 1, step 7, to give 7/0 product in 7095 yield.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 9295. MS high-resolution calculations. for

ISa7NzBSIMO, ANI 667.2141, found 667.2137.

Example 294: 7542-11 -benzhydryl-5-chloro-2-(2-4(1-methyl-1H-imidazol-2-yl)usulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoin acid

Stage 1: This compound is obtained from methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoate (stage b, example 1) and 1 -methyl-1H-imidazole-2-sulfonyl chloride by the procedure of Example 1, step 7, to give the product with a yield of 76905.

Stage 2: The intermediate compound, which is a complex ester, is hydrolyzed in accordance with stage 8 of example 1, obtaining the acid indicated in the title with a yield of 8795. MS high-resolution calculations. for

ISzvNzzSIMAO5 ANI 669,1933 found 669,1933.

Example 295: 4-(3-/1-benzhydryl-2-(2-(2-chlorophenyl)sulfonyl|iamino)ethyl)-1H-indol-3-yl|Ipropyl)benzoic acid c

Stage 1: A mixture of methyl-4-iodobenzoate (5.3g, 20.2mmol), allyl alcohol (1.78g, 30.3mmol), Manso uz (4.24g, 50.5mmol), RY(OAc) (0 ,14g, 0.bOmmol), (n-Vy)AMVg (6.55g, 20.2mmol) and molecular sieves 4-A (41g) in i) anhydrous DMF (bO9ml) are stirred at room temperature for 4 days. The reaction mixture is filtered through celite, the filtrate is poured into water and extracted with EIUAs. The organic layer was washed with a saturated salt solution, dried (Ma»3O)) and concentrated in vacuo. Flash chromatography (silica gel, 10-2095 E (Ods/hexanes) gives 2x11 g (8595 based on the reduced starting substance) of the desired methyl ester of 4-(3-oxopropyl)benzoic acid in the form of a transparent oily substance. -

Stage 2: To a solution of 2-methyl-1H-indole (0.8g, 5.2mmol) and 4-(3-oxopropyl)benzoic acid methyl ether (1.0g, 5.2mmol) in methylene chloride (bOml) is added TFO (1.78g, 15.mmol), followed by the addition of triethylsilane (1.81g, 15.6mmol). The reaction mixture is stirred overnight, quenched with a saturated solution of

Manso" (5 Oml) and the organic layer is washed with saturated solution of Manso", water, saturated salt solution and dried (Ma»5O)). The solvent is removed under reduced pressure and the residue is purified by flash column chromatography using a mixture of 10-2095 E(OAc/hexanes) to give the desired 4-I(3-(2-methyl-1H-indol-3-yl)propyl|benzoic acid methyl ether acid with a yield of 88905 (1.67 g).

Stage C: To a solution of the product from the previous stage 2 (1.66g, 4.8bmmol) in DMF (20ml) is added Mann (6095 in mineral oil, 0.24g, 5.83mmol) under Mo atmosphere. The mixture was stirred for 1 hour at room temperature, after which benzhydryl bromide (1.8 g, 7.29 mmol) in DMF (5 mL) was added dropwise. This reactionary. the mixture is stirred overnight at room temperature. Add water (500 ml) to the reaction mixture and extracted with EtOAc, washed with saturated salt solution, dried (Ma»SO)) and concentrated under reduced pressure to a brown syrup, which was purified by chromatography on silica gel using a mixture of 1095 EtOAc/hexanes as eluent to isolate the methyl ether -I 4-I3-( 1-benzhydryl-2-methyl-1H-indole-3-yl)upropyl|Isenzoic acid in the form of a solid white substance with a yield of 7690 (1.47 g). - Stage 4: The product from the previous stage (1.46g, 2.87mmol) is dissolved in SSI in (14.5ml), after which their MV (1.02g, 5.7mmol) and benzoyl peroxide (2mg) are added. The reaction mixture is boiled under reflux for 5 minutes for 1 hour (until all the starting substance disappears). This mixture is cooled to room temperature,

Sh- is filtered and the solid is washed with SSRI)/. The filtrate is evaporated to a brown residue, which is dissolved

Ge in a mixture of acetone (40 ml) and water (4 ml), then AdeoSO 3 (1.75 g, 3.1 mmol) is added to this solution, and after stirring overnight at room temperature, it is filtered through celite, the solvent is evaporated under reduced pressure and until water is added to the residue. The mixture is extracted with EtOAc, washed with a saturated salt solution, stirred (Ma»3ZO)) and evaporated to a syrup, which is purified with a mixture of 1095 EtOAc/hexanes, releasing the methyl ether 4-I3-(1-benzhydryl-2-formyl-1H- indol-3-yl)/propyl|benzoic acid (1.13 g) with a yield of 8595. Alternatively, (F, dibromide from the reaction with M-bromosuccinimide can be poured into DMSO (10-2095 mass concentration) and stirred for 30 minutes at room temperature After the completion of the reaction, the reaction mixture is poured into water and the precipitate obtained as a result is separated by filtration, the precipitate on the filter is washed with water and dried, obtaining essentially a quantitative yield.

Stage 5: MNAOAc (0.077g, 1mmol) is added to the solution of indole from the previous stage (0.52g, 1mmol) in SNUMO" (6b, 2ml), the mixture is refluxed for 1 hour, then MH OAc (0.077 g, 1 mmol), the mixture is continued to reflux for an additional 1 hour, MNAaOSAC (0.077 g, Tmmol) is added again and heating is continued for an additional 1 hour. The reaction mixture 65 is allowed to cool to room temperature, E(OAc (500 ml) is added, followed by the addition of 100 ml of water. The aqueous layer is extracted with EOAc and the combined organic layers are washed with saturated salt solution, dried (Ma»520),) and evaporated to form yellow foam, which is subjected to chromatographic purification using mixture 1090

EtOAc/hexanes as eluent to give 4-(3-β1-benzhydryl-2-(2-nitrovinyl)-1H-indol-3-yl|Ipropyl)benzoic acid methyl ester as a yellow foam in a yield of 500 Toto (0.38G ).

Stage 6: 7p(No) is obtained by adding Nasi" (3.4g, 7.2mmol) to a mixture of dust 2p (34.68g, 530.35mmol) and 590

NOI (Zvml) in a 100 ml flask, and this mixture is vigorously stirred for 1 hour. The aqueous phase is decanted, Zvml 595 NSI is added again and the mixture is stirred for 1 hour. The aqueous phase is decanted. This solid was added to vinyl nitro compound 6 (15g, 26.57mmol) in THF (bbOml) and concentrated HCl (64.5ml). This mixture is stirred at room temperature for 1 hour, then refluxed for 15 minutes. The reaction mixture is cooled to room temperature and filtered through celite. An aqueous solution of МН.АОН (200 ml) is added to the filtrate, stirred for 15 minutes. and THF is removed under reduced pressure. The aqueous layer is extracted with CHCl3, the combined organic layer is washed with saturated salt solution, dried (Ma»2), and concentrated to a brown foam, which is purified by column chromatography, first eluting the CHCl3 /5 column to remove non-polar impurities, then with a mixture of 295 Meon /cSnNeIi with to isolate the desired 4-3-(2-(2-aminoethyl)-1-benzhydryl-1H-indol-3-yl|Ipropyl)benzoic acid methyl ester in a yield of 4095 (6.1g).

Stage 7: To amine (1.0 equiv.;) and saturated Manso 3 (014M) in SNS". (0.07M) add 2-chlorobenzenesulfonyl chloride (1.0 equiv.). After 1 hour, the mixture is poured into a saturated solution of sodium bicarbonate and extracted with СНоСи». The combined organic phase is washed with saturated salt solution, dried over 20 sodium sulfate and purified by column chromatography to give 9295 of the desired methyl ester 4-(3-71-benzhydryl-2-(2-(2-chlorobenzenesulfonylamino)ethyl)/|-1H- indole-Z3-ylpropyl)benzoic acid.

Step 8: The resulting ester is hydrolyzed by mixing with Mahon's yin (bq.) in THF (0.07M) and enough MeOH to give a clear solution. The reaction is controlled by TLC (1090

Meon-СНХСІІ») after the disappearance of the original substance. The mixture is stirred overnight at room temperature and the mixture is then concentrated, diluted with HO and acidified to pH 2-4 using 1M HCl. The aqueous phase is extracted

EtOAc and the organic phase are washed with a saturated salt solution, dried over sodium sulfate and concentrated, i) obtaining the title compound with a yield of 5690. t/2 (M-1) 663.2.

Example 296: 4-2-(1-benzhydryl-5-chloro-2-(2-1(3,4-dichlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)-2-fluorobenzoin with zo Acid

Stage 1: ((3,4-dichlorophenyl)methyl|sulfonyl chloride (0.07g, O0.24mmol) is added to the mixture with stirring - ethyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5- chloro-1H-indol-3-yl|ethoxy)-2-fluorobenzoate (stage b, example 190, "g 0.17g, 0.2mmol) and KSO" (0.055g, 0.4mmol) in a mixture of CHClCl" (2ml ) and water (0.7 ml). After 2 hours at room temperature, the mixture is extracted with СНоSiO (10ml) and the extract is washed with 0.5N Mahon, saturated salt solution and dried over sodium sulfate. The СНоСі solution is filtered through silica gel and the filtrate is evaporated . 1H-indole-3-yl|ethoxy)-2-fluorobenzoate as a solid white substance; Tl -83-852S; MS of high resolution calculations. for S.4NzvSiIzeMoOv 792.1395 found (ERI) 793.14729. "

Stage 2: Ethyl sshc 4-2-P1-benzhydryl-5-chloro-2-(2-11(3,4-dichlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)-2 -fluorobenzoate (0.11g, 0.14mmol), THF (0.5ml), MeOH (0.5ml) and ion Mahon (0.5ml) were stirred together overnight. Solvents are removed and the resulting residue is transferred to water. The solution is acidified with Mn HCIII 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 0.1 g - and 4-2-P1-benzhydryl-5-chloro-2-(2-1(3,4-dichlorobenzyl)sulfonyl|amino)ethyl)-1H -indole-3-yl|ethoxy)-2-fluorobenzoic acid in the form of a solid white substance; T dl.-117-1199C; MS of high resolution calculations. for - SzeNz»SiIZEM2O55 764.1082, found (ERYCH) 787.09794. Example 2917: 4-2-1-benzhydryl-5-chloro-2-(2-((2-chlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl ethoxy)-2-fluorobenzoic acid and Stage 1: (2-chlorophenyl)methyl|sulfonyl chloride (0.14 g, 0.5 mmol) is added to the ethyl mixture with stirring

IZ 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)-2-fluorobenzoate (stage b, example 190, 0.12g,

O.2 mmol) and K»CO3 (0.11 g, O.vmmol) in a mixture of CHNSiO (2 ml) and water (I ml). After 2 hours at room temperature, the mixture is extracted with СНоСиИ» (1 Oml) and the extract is washed with 0.5N Mahon, a saturated salt solution and dried over sodium sulfate. The solution of СНоSiO is filtered 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 o 4-2-/1-benzhydryl-5-chloro-2-(2-CH(2-chlorobenzyl)sulfonyl|amino)ethyl)-1H- indole-3-yl|ethoxy)-2-fluorobenzoate in the form of a solid white substance.

Stage 2: Ethyl in 4-(2-(1-benzhydryl-5-chloro-2-(2-C(2-chlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)-2- fluorobenzoate (0.06g, 0.1mmol), THF (0.5ml), MeOnH (0.5ml) and ion Mahon (0.5ml) were stirred together overnight. Solvents are removed and the resulting residue is transferred to water. The solution is acidified with Mn HCIII and extracted with ethyl acetate. The extract is dried over sodium sulfate and evaporated. The residue obtained as a result is triturated in a mixture of ether and hexane, obtaining О,obg вЕ /4-2-/1-benzhydryl-5-chloro-2-(2-1(2-chlorobenzyl)sulfonyl|amino)ethyl)-1H- indole-3-yl|ethoxy)-2-fluorobenzoic acid in the form of a solid off-white substance; T dl.-132-13592S; MO (ERY) t/2 729.74 ((М-Н)-); MS of high resolution calculations. for SzoNzzSi2EMoOvBZ 730.1471, found (ERI) 731.15514.

Example 298: 3-I4-(42-(/1-benzhydryl-5-chloro-2-(2-1(3,4-dichlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-ylylethyl)isulfonyl) phenyl l|-2,2-dimethylpropanoic acid

Stage 1: |((3,4-chlorophenyl)methyl|sulfonyl chloride (0.06 mg, 0.2 mmol) with stirring is added to the mixture of ethyl 3-(4-2-(2-(2-aminoethyl)-1-benzhydryl- 5-Chloro-1H-indol-3-yl(yl)-2,2-dimethylpropionate (0.09g, 0.14mmol) and KSO" (0.04g, 0.28mmol) in a mixture of СНоSiO" (2ml) and water (0.7ml). After 2 hours at room temperature, the mixture is extracted with SiOCl" (10ml) and the extract is washed with 0.5N Mahon saturated solution of 7/0 bol and dried over sodium sulfate. The SiOCl" solution is filtered through silica gel and the filtrate is evaporated.

The resulting residue is triturated in a mixture of ether and hexanes, obtaining 0.04 g of ethyl 3-I4-(42-(/1-benzhydryl-5-chloro-2-(2-1(3,4-dichlorobenzyl)sulfonyl|amino) ethyl)-1H-indol-3-ylylethyl)isulfonyl)phenyl)-2,2-dimethylpropanoate as a white solid.

Stage 2: Ethyl 3-I4-(42-(/1-benzhydryl-5-chloro-2-(2-1(3,4-dichlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-ylylethyl)isulfonyl )phenyl l|-2,2-dimethylpropanoate (0.04 g, 0.0 mmol), THF (0.0 bml), MeOH (0.bml) and ion Mahon (0.5 ml) were stirred overnight. Solvents are removed and the resulting residue is transferred to water. The solution is acidified with NHCl 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 hexanes, obtaining O,O4g 3-I4-(42-(/1-benzhydryl-5-chloro-2-(2-1(3,4-dichlorobenzyl)sulfonyl|amino)ethyl )-1H-indol-3-ylylethyl)isulfonyl)phenyl-2,2-dimethylpropanoic acid in the form of a solid white substance; Tll.-207-2082C; MS (ERY) t/2 849.1 (M-N);

MS of high resolution calculations. for S/zNAISIzMoOv5" 850.1472, found (ERY) 851.1545.

Example 299: 4-2-(1-benzhydryl-5-chloro-2-(2-1(3,4-dichlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)-2-methoxybenzo with acid

Stage 1: Methyl ether of 2,4-dihydroxybenzoic acid (11.7b6g, 7Omol) is dissolved in EG2O (175ml). at

Then add EBM (10.78ml, 7/mmol), AcSO (7.28ml, 7/mmol) and OMAR (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 is purified on a silica gel column using dichloromethane as an eluent. 3.44 g of 4-acetoxy-2-hydroxybenzoic acid methyl ether are obtained with a yield of 23905. -

Step 2: To a mixture of the product from step 1 (0.962g, 4.bmmol), RAZR (1.79g, b.0mmol) and dichloromethane (10ml) was added Meon (0.3ml, 7.4mmol). Then OEAO (1.32 ml, 8.4 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 4 days. The reaction solution is concentrated on a rotary -

35 in the evaporator and the resulting residue is purified on silica gel preparative plates using a 1:3 mixture of EtOAc/hexane as an eluent. 1.10 g of 4-acetoxy-2-methoxybenzoic acid methyl ether are obtained in quantitative yield.

Stage C: To a solution of the product from stage 2 (1.10g, 4.9mmol) in a mixture of THF (Iml) and Meon (ml) add 0.Tn

Mmaon (1Oml, Immol). The reaction mixture was 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 in c is neutralized by NH, and a precipitate falls out. The sediment is collected and washed with water and hexane. 0.29 g of methyl ether of 4-hydroxy-2-methoxybenzoic acid are obtained with a yield of 3390. "" Stage 4: To a mixture of methyl ether of 4-hydroxy-2-methoxybenzoic acid (0.29 g, 1.bmol), RA ZR (0.312 g, 1.2 mmol) and dichloromethane (1 Oml) add 2-41-benzhydryl-2-(2-(tert-butyldiphenylsilanyloxy)ethyl)|-5-chloro-1H-indol-3-yl)ethanol (stage b, example 142, and 0.503 g, 0.78 mmol). Then OEAO (0.2 ml, 1.3 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature overnight. The reaction solution is concentrated on a rotary evaporator and the resulting residue is purified on silica gel preparative plates using dichloromethane as the eluent. O, g of methyl ether 5o0 4-(2-41-benzhydryl-2-(2-(tert-butyldiphenylsilanyloxy)ethyl)|-5-chloro-1H-indol-3-yl) is obtained. ethoxy)-2-ethoxybenzoic acid with a yield of 4095. from Stage 5: To a solution of methyl ether 4-(2-71-benzhydryl-2-(2-(tert-butyldiphenylsilanyloxy)ethyl|-5-chloro-1H-indole- To 3-yl)ethoxy)-2-ethoxybenzoic acid (0.25g, 0.000 mmol) in THF (4 mL) was added TVAE (1M in THF) (0.37 mL, 0.37 mmol). The reaction mixture is stirred at room temperature for 30 minutes. The reaction solution is concentrated on a rotary evaporator and the resulting residue is purified on silica gel preparative plates, iF) using a 1:19 mixture of E(OAc/dichloromethane as an eluent. 0.11 g of methyl ether 4-2-11-benzhydryl-5-chloro is obtained -2-(2-hydroxyethyl)-1H-indole-3-yl|ethoxy)-2-methoxybenzoic acid (white solid) with a yield of 6290 g. Stage 6: To the solution of the alcohol from stage 5 (0.11 g, O, 1U9mmol) in dichloromethane (dml) at 02С add Mebsi (0.03ml, 0.39mmol) and EBM (0.07ml, 0.48mmol). The reaction mixture was stirred at 09C for 1 hour and then warmed to room temperature and stirred for an additional hour. The reaction solution is concentrated on a rotary evaporator. 0.123 g of methyl ester of 4-2-/1-benzhydryl-5-chloro-2-(2-methanesulfonyloxyethyl)-1H-indol-3-yl|ethoxy)-2-methoxybenzoic acid is obtained with a quantitative yield of 65.

Step 7: The mesylate from the previous step (0.123g, 0.19mmol) is dissolved in DMF (ml). They add Mam from

(0.065g, 1.0mmol), the mixture is heated to 602C and stirred for 3 hours. The reaction mixture is cooled to room temperature and water is added. E(OAc) is extracted and the organic layer is washed with a saturated salt solution. The organic layer is dried over sodium sulfate, filtered and concentrated on a rotary evaporator.

They are additionally dried under a strong vacuum. 0.110 g of methyl ester of 4-2-(2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)-2-methoxybenzoic acid is obtained with a yield of 9790.

Stage 8: To a solution of azide from stage 7 (0.110 g, 0.18 mmol) in THF (2 ml) add RI zR (polymer carrier:

Zmmol RAZR/gram) (0.110 g, 0.3 Zmmol). The reaction mixture is stirred at room temperature for 24 hours. Then water (0.5 ml) is added and the reaction mixture is stirred at room temperature overnight. 7/0 The reaction solution is filtered and the filtrate is concentrated on a rotary evaporator. The resulting residue is purified on silica gel preparative plates using 296 Meon in dichloromethane as eluent. 0.012 g of 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)-2-methoxybenzoic acid methyl ester is obtained with a yield of 1290.

Stage 9: To a solution of the amine from stage 8 (0.012g, 0.021mmol) and ((3,4-dichlorophenyl)methyl|sulfonyl chloride 75 (0.010g, 0.039mmol) in dichloromethane (2ml) add a saturated aqueous solution of Ma»2CO3 (2ml ). The reaction mixture is 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 silica gel preparative plates, using 295 MeON in dichloromethane as eluent, afforded 9.016 g of the desired sulfonamide (white solid) in a yield of 9690. t/2 (M'k1) 793.

Stage 10: To a solution of the complex ester from stage 9 (0.016g, 0.02O0mmol) in a mixture of THF (Iml) and MeonH (ml) add in Maon (ml). The reaction mixture was stirred at room temperature for 5 days. THF and Meon are removed on a rotary evaporator. Extract with dichloromethane, separate and concentrate the aqueous layer.

The aqueous layer is neutralized with HC and the precipitate obtained as a result is collected. 0.013 g of the acid specified in the Title (solid yellow substance) are obtained with a yield of 8490. t/2 (M-1) 777.

Example C00: i) 4-2-P1-benzhydryl-5-chloro-2-(2-1(3,4-dichlorobenzyl)sulfonyl|amino)ethyl)-1H-indole-3-yl|ethoxy)-2- isopropoxybenzoic acid

Stage 1: Isopropanol ( 0.6 ml, 8.2 mmol). Then OEAO (1.12 ml, 7.1 mmol) was added to the reaction mixture. The reaction mixture is stirred at room temperature for 2 days. The reaction solution is concentrated on a rotary evaporator and the resulting residue is purified on silica gel preparative plates using a 1:5 E(JudAc/hexane) mixture as an eluent.

1.11 g of 4-acetoxy-2-isopropoxybenzoic acid methyl ester are obtained with a yield of 7990.

Stage 2: To a solution of methyl ether of 4-acetoxy-2-isopropoxybenzoic acid (0.910 g, 33, bml) in a mixture of

THF (Iml) and Meon (ml) add O,in MaonN. 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 by NOI, and a precipitate is formed. The precipitate is collected and washed with water and hexane. 0.870 g of methyl ester of 4-hydroxy-2-isopropoxybenzoic acid is obtained in quantitative yield. "

Stage 3: 2-(1-benzhydryl-2 -(2-(tert-butyldiphenylsilanyloxy)ethyl/|-5-chloro-1H-indole-3-ylethanol (stage 6, example 142, "" 0.500g, 0.78mmol). Then OEAO (0, 2ml, 1.3mmol). The reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated on a rotary evaporator and the obtained

As a result, the residue is purified on silica gel preparative plates, using dichloromethane as an eluent. 0.20 g of methyl ether 4-(2-71-benzhydryl-2-(2-(tert-butyldiphenylsilanyloxy)ethyl|-5-chloro-1H-indol-3-yl) is obtained

of ethoxy)-2-isopropoxybenzoic acid with a yield of 31965. g» Stage 4: To a solution of the silyl ether from stage C (0.20g, O0.24mmol) in THF (4ml) add TVAE (IM in THF) (0.29ml, 0.29 mmol). The reaction mixture is stirred at room temperature for 30 minutes. The reaction mixture and the solution are concentrated on a rotary evaporator, and the resulting residue is purified on silica gel from preparative plates, using a 1:9 E(OAc/dichloromethane mixture as an eluent. 0.10 g of methyl ether 4-2-11-benzhydryl-5-chloro- 2-(2-Hydroxyethyl)-1H-indol-3-yl|ethoxy)-2-isopropoxybenzoic acid (brown solid) in a yield of 70905.

Stage 5: To a solution of alcohol from stage 4 (0.10g, 0.17mmol) in dichloromethane (dml) at 09C, methanesulfonyl chloride (0.03ml, 0.39mmol) and EB6M (0.0bml, 0.4zmmol) are added. The reaction mixture was stirred at 09°C for 1 hour and then warmed to room temperature and stirred for an additional hour. (name) The reaction solution is concentrated on a rotary evaporator. 0.115 g of methyl ester of 4-2-11-benzhydryl-5-chloro-2-(2-methanesulfonyloxyethyl)-1H-indol-3-yl|ethoxy)-2-isopropoxybenzoic acid with 60 quantitative yield is obtained.

Stage b: Mesylate from stage 5 (0.115g, O0.17mmol) is dissolved in DMF (5ml). Mam z (0.065g, 1.0mol) is added, the mixture is heated to 602 and stirred for 3 hours. The reaction mixture is cooled to room temperature and water is added. Extracted with ethyl acetate and the organic layer was washed with a saturated salt solution.

The organic layer is dried over sodium sulfate, filtered and concentrated on a rotary evaporator. Additionally, 65 is dried under high vacuum. 0.100 g of 4-2-(2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-ylliethoxy)-2-isopropoxybenzoic acid methyl ester is obtained with a yield of 94965.

Stage 7: RA ZR (polymer carrier:

Zmmol RAZR/gram) (0.100g, O.ZOmmol). The reaction mixture is stirred at room temperature for 24 hours. Then water (0.5 ml) is added and the reaction mixture is stirred at room temperature overnight.

The reaction solution is filtered and the filtrate is concentrated on a rotary evaporator. The resulting residue is purified on silica gel preparative plates using 296 Meon in dichloromethane as eluent. 0.020 g of 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)-2-isopropoxybenzoic acid methyl ester is obtained with a yield of 21905.

Stage 8: To a solution of the amine from stage 1 (0.020g, 0.034mmol) and ((3,4-dichlorophenyl)methyl|sulfonyl chloride 7/0 (0.015g, 0.058mmol) in dichloromethane (2ml) add a saturated aqueous solution of Ma» -CO3 (2 ml). The reaction mixture is 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 silica gel preparative plates, using 295 MeON in dichloromethane as eluent.75 9.022 g of the desired sulfonamide (white solid) were obtained in a yield of 79905. t/2 (M'-1) 821.

Stage 9: To a solution of the ester from stage 8 (0.022g, 0.027mmol) in a mixture of THF (Iml) and Meon (Iml) add Masson's (ml). The reaction mixture is stirred at room temperature for 5 days. THF and meon are removed on a rotary evaporator. Extract with dichloromethane, separate and collect the aqueous layer.

The aqueous layer is neutralized with HC and the precipitate obtained as a result is collected. 0.021 g of the acid indicated in title 2 (solid yellow substance) is obtained with a yield of 9670. t/2 (M-1) 805.

Activity analysis

Coumarin assay 7-Hydroxycoumarinyl-β6-heptenoate is used as a monomeric substrate for SRIA 5", as previously reported by Iniapo, 7. ei ai., 1994, Apaiuiisa! Viospetivhigu 222, 110-115). Inhibitors are mixed with 200 μl of sample buffer (8 Ωm Nerea, pH 7.5, imm EOTA) containing bΩm 7-hydroxycoumarinyl-b-heptenoate. The reaction is initiated by adding 4 μg of SRIA" to 1 μg of sample buffer. Hydrolysis of the ester of 7-hydroxycoumarinyl-b-heptenoate i) is monitored with a fluorometer, performing excitation at Zbonm and measuring the release at 4bOnm. Enzyme activity is proportional to the increase in release at 4 bOhm per minute. In the presence of the SRI A" inhibitor, the rate of increase is lower. with

Example Mo Coumarin Isvo (μM) Example 231.15 - pone ny tny yy m zv (Example 00025 0000 Pryshado) 08 im

Pryayuedi | 3 Devices 08 h 4 Z s. » 1 - Priledlja| 008 Device ze| 032 tsi i. 4" exit Priledav 235 Priledea 08 o

Priledo 059 Priledev 055 tvo bo Example 58 0.36 Example 104 1.1

Example in 0500 Prytedliv 09 and 2

Priediv lake Priedi 06 pm 25 o'clock

Pryakleadya 006000 Pryedio 02 h with Pred 0012000 Pryedosa 009 h with h with c « i with s

And" - in m with

V. che (Example 157. 02 Example ?203, 069 o yu bo b5 ole-107-

Example 170 0.95 Example 216 was not determined

(Example 177) 09 Example? 06 o'clock Pryakadito| 00090 Pryfedoov| 04 (Example 82) 06 Example 04 and 20 cm 5 o

Example yaz 00075 0 Prifedove 09 sch zo Example 25 009 Device 21 che determined m z m z tsi « yu Z s Pryaklvdovvv 0050

Translated 106001

And" Pryshadovt! b51

Showcase 1

Example 002 - Pryaklvdoy 031

An example! 0251 in Pryaklvdov; 0531 g Example 031 I Prepositions 00401

V. Pryaklvdovv 031 from Prikladovv| blah

Pryaklvdovy 0041

Example 009

Example 0501 about Preposition la

Pryatadomi 01501 t Pryalvdotyu 001

Application 001 bo (Example 274) was not determined by the row

Application 031

Example от) бе11 65 Compounds according to the invention inhibit the activity of sRI A", which is required for the delivery of the arachidonic acid substrate to cyclooxygenase-1 or -2 and 5-lipoxygenase, which in turn initiate the production of prostaglandins and leukotrienes, respectively. In addition, the activity of SRIA" is important for the production of lysophospholipid, which is the precursor of RABE. Thus, these compounds are applicable for the treatment and prevention of pathological conditions in which leukotrienes, prostaglandins or PAP are included. Moreover, in diseases in which more than one of these agents play a role, a CRI A inhibitor is expected to be more effective than leukotriene, prostaglandin, or RAB receptor antagonists, and more effective than cyclooxygenase or 5-lipoxygenase inhibitors.

Therefore, the compounds, pharmaceutical compositions and regimens according to the present invention are applicable for the treatment and prevention of disorders that can be treated with inhibitors of cyclooxygenase-2, cyclooxygenase-1 and 7/0 5-lipoxygenase, as well as antagonists of RAE, leukotriene, or prostaglandin receptors. Diseases that can be treated with the compounds of the present invention include, but are not limited to, pulmonary disorders including diseases such as asthma, chronic bronchitis, and familial obstructive airway disease; allergies and allergic reactions, such as allergic rhinitis, contact dermatitis, allergic conjunctivitis and the like; inflammation, such as arthritis or inflammatory bowel disease; skin disorders such as psoriasis, atopic eczema, acne, UV damage, burns and dermatitis; cardiovascular diseases, such as atherosclerosis, angina pectoris, myocardial ischemia, hypertension, platelet aggregation and the like; and immunologically or chemically induced renal failure. Medicines can also be cytoprotective, preventing damage to the mucous membrane of the gastrointestinal tract by harmful factors. The compounds will also be useful in 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, alleviating or alleviating asthma according to the present invention include methods of treating acquired bronchial asthma (also known as allergic asthma or atopic asthma), hereditary bronchial asthma (also known as non-allergic asthma or non-atopic asthma) or combinations thereof, called mixed asthma Conditions in patients experiencing or exposed to acquired or systemic apergic asthma include those caused by or associated with multiple allergens such as pollen, spores, grass or weeds, pet dander, dust, mites, etc. . Because allergens and other irritants i) themselves are present at different times throughout the year, these types of cases are also called seasonal asthma. The group of acquired asthma also includes bronchial asthma and allergic aspergillosis of the bronchi and lungs.

Hereditary asthma that can be treated or alleviated with these methods includes cases caused by infectious agents such as colds and flu in adults and respiratory syncytial virus (RSV), rhinovirus, and influenza virus common in children. Also includes asthmatic conditions, which can be - caused in some asthmatics by exercise and/or cold air. The methods are applicable for the treatment of inherited asthma associated with industrial or occupational exposures such as smog, ozone, noxious gases, sulfur dioxide, nitrogen oxide, fumes including isocyanates, paint fumes, plastics, etc. polyurethanes, varnishes, etc., wood, vegetable dust or other organic dust, etc. The methods are also applicable for asthmatic cases associated with food additives, preservatives and pharmacological preparations.

Common substances of these types are food dyes such as tartrazine, preservatives similar to bisulfites and metabisulfites, and pharmacological agents such as aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs).

Also included are methods of treating, suppressing, or alleviating types of asthma called "hidden asthma" or cough variant asthma. The methods described herein are also applicable to the treatment or alleviation of hereditary asthma associated with . gastroesophageal reflux (GER), which can stimulate bronchostenosis. SECO, together with the dependents and? secretions, suppressed coughs, and exposure to allergens and irritants in the bedroom can contribute to asthmatic conditions and is called nocturnal asthma or MosiigpaI asthma. In methods of treating, suppressing, or ameliorating asthma associated with SECO, a pharmaceutically effective amount of a compound of the present invention may be used as described herein in combination with a pharmaceutically effective amount of a drug to treat SECO. These drugs include, but are not limited to, proton pump inhibitors

Sh- pumps, similar to pantoprazole sodium delayed-action tablets of the RKOTOMIHF brand, their omeprazole slow-acting capsules of the RKI/OBESF brand, rebeprazole sodium tablets of delayed action 5r of the ASIRNEHO brand or lansoprazole slow-acting capsules of the RKEMASIYUOF brand)

Sh- These compounds will be particularly suitable for the treatment of arthritic and/or rheumatic disorders which

These include, but are not limited to, rheumatoid arthritis, spondyloarthropathy, gouty arthritis, osteoarthritis, systemic lupus erythematosus, and Steele's disease. The compounds of the present invention will be useful in the treatment of post-operative inflammation, including inflammation following ophthalmic surgery such as cataract surgery or refractive surgery.

The compounds of the present invention can be used as an antipyretic. Compounds of the present invention may be used in methods of treating 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 structural or soft tissue injury, pain associated with progressive diseases such as cancer and degenerative diseases, neuropathic pain, which may include acute pain such as acute injury or trauma, pre- and post-operative pain, migraine pain, toothache, etc., chronic pain such as neuropathic conditions of diabetic peripheral neuropathy, post-herpetic neuralgia, fibromyalgia, and inflammatory conditions such as osteoarthritis and rheumatic arthritis, due to acute injury or trauma and pain, 65 associated with carcinoma.

The present invention further provides a method of alleviating, suppressing, ameliorating or treating arthritic and rheumatic disorders in a mammal, the method comprising administering to the mammal in need thereof a pharmaceutically effective amount of a chemical inhibitor of phospholipase enzymes, particularly phospholipase A enzymes, as defined herein, and a pharmaceutically effective amount of antirheumatic drug.

Combinations for the treatment of arthritic and rheumatic disorders may include, but are not limited to, over-the-counter antirheumatic drugs such as naproxen, available as ES-MARCOZUMO delayed-release tablets, MARCOZUMO, AMARCOHO, and AMARCOHOF O5 tablets, and Cospe's MARCOBUMO suspension And arz, celecoxib tablets of the trade mark CE GEVKEHF, rofecoxib of the trade mark MIOXHF, betamethasone of the trade mark CE 'EZTOMEF, penicillamine capsules of the trade mark SORKAMIMEF, 7/0 penicillamine tablets of the trade mark OEREMO, suspension for injection of methylprednisolone acetate OEROMEOKOG, tablets of leflunomide trade mark AKAMAtmM, sulfasalazine delayed-release tablets of the trade mark

ADOYIRIOPME EM-gareF, piroxicam capsules of the trade mark RE OEMEF, diclofenac potassium tablets

SATAB AM K. tablets of diclofenac sodium of delayed action MY TAKEMEYA, tablets of diclofenac sodium of prolonged action MY TAKEMF-HC, Etanresept products of EMVKEG There are 75 anti-rheumatic drugs available for sale.

Also applicable are cyclosprin capsules of the trade mark SEMOKAREtm, sirolimus products of the trade mark KARAMIMEF, capsules or oral solution of cyclosprin of the trade mark MEOKAIIF, tablets or IM injection of azathioprine of the trade mark IMOKAM I, capsules, oral suspension and suppositories of the trade mark

IMOOSIMFO, prednisolone sodium phosphate oral solution REFBIAREYUOF,, hydroxychloroquine sulfate of the trade mark RGIAOSHEMII F, prednisone syrup of the trade mark RKEGOMEF, infliximab recombinant for IM injection

KEMISAOEEF and methylprednisolone sodium succinate for injections ZOYA O-MEOKOY! F.

Also useful in combinations according to the present invention are gold compounds and products useful in the treatment of arthritis and rheumatic conditions, such as auranovine or sodium gold thiomalate injection (MUOSNKIZMIMEF)

Each of these products can be administered in pharmaceutically effective doses and methods of application, Hey! known from the state of the art, such as those described for the products in |Rpuzisiap YuOevzK Keiegepse, 55 Edyop, 2001, (5)

Medicine! Esopotisv So., Ips., Mopimaie, M...

Compounds of the present invention may also be administered by the methods of the present invention with analgesic and anti-inflammatory drugs such as NSAIDs (MAOIs), aspirin and other salicylates.

Examples of applicable drugs include ibuprofen (MOTKIMF, AOMITSF), naproxen (MARKOSUMF), sulindac (SGYMOKIIA), diclofenac (MOI TAKEMFE), piroxicam (REGOEEMEF), ketoprofen (OKIBIZF), m diflunisal (OYI OVIOF), nabumeton (KEGAREMF), etodolac (I O0BIMEF), oxaprozin (PAURKOF), indomethacin (IMOOSIMF)), melicoxam (MOVISOKHF)), valdecoxib and eterocoxib. Aspirin is an anti-inflammatory drug when given in high doses, otherwise it is simply a pain reliever, similar to acetaminophen (TM EMO F). m

Suitable cyclooxygenase 2 (COX-2) inhibitors for use with the methods of the present invention include, but are not limited to, 2-(4-ethoxyphenyl)-3-(4-methanesulfonylphenyl)pyrazolo|1,5-b|pyridazine, -

СОС-501, celecoxib, СОХ-189, 4-(2-oxo-3-phenyl-2,3-dihydrooxazol-4-yl)benzenesulfonamide, С5-179, С5-502, 0-1367, darbufelon, OER, OKE -4367, flozulide, L/TE-522 (4-(4-cyclohexyl-2-methyl-5-oxazolyl)-2-fluorobenzenesulfonamide), 1-745337, 1-768277, 1-776967, 1-783003, "

I -791456, Ii -804600, meloxicam, Mk (etoricoxib), nimesulide, M5-398, parecoxib, 1-methylsulfonyl-4-(1,1-dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-diene -3-yl)benzene, - c 4-(1,5-dihydro-6-fluoro-7-methoxy-3-"(trifluoromethyl)-(2)-benzothiogarane-(4,3-y)pyrazol-1- yl)benzenesulfonamide, and 4,4-dimethyl-2-phenyl-3-(4-methylsulfonyl)phenyl)cyclobutenone, ,» 4-amino-M-(4-(2-fluoro-5-trifluoromethyl)-thiazole-2 -yl)benzenesulfonamide, 1-(7-tert-butyl-2,3-dihydro-3,3-dimethyl-5-benzofuranyl)-4-cyclopropylbutan-1-one, Ppagtargo|esiv Mo6bo89 (Koyuriki Ppagtaseciisa!), K5Z -113472, KMU.-63556, 5-2474, 5-33516, 560-299, 5060-5755, valdecoxib, OMK-8877, -| k-8813, OK-8880. Further suitable COX-2 inhibitors for use in accordance with the invention include parecoxib,

MKbv63, 4-(4-cyclohexyl-2-methyl-5-oxazolyl)-2-fluorobenzenesulfonamide (TE-522), nimesulide, flozulide, OER and 2-(4-ethoxyphenyl)-3-(4-methanesulfonylphenyl)pyrazolo| 1,5-B|Ipyridazine and their physiologically acceptable salts, esters or solvates. -1 50 Such compositions are also applicable in the treatment of menstrual cramps, premature birth, tendonitis, bursitis, allergic neuritis, cytomegalovirus infection, apoptosis, including ViL-induced apoptosis,

Ko) lumbago, liver disease, including hepatitis.

The methods are also useful for the treatment of gastrointestinal conditions such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis and for the prevention or treatment of cancer such as rectal cancer. The compounds and compositions of the present invention are also applicable for the prevention or treatment of benign and malignant tumor/neoplasia, including cancer such as rectal cancer, brain cancer, bone cancer, epithelial cell neoplasia (epithelial carcinoma) such as basal cell carcinoma cells, adenocarcinoma, cancer of the gastrointestinal tract, including lip cancer, oral cavity cancer, esophageal cancer, small bowel cancer and stomach cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer , lung cancer, breast cancer, and skin cancer such as squamous cell carcinoma and basal cell carcinoma, prostate cancer, renal cell carcinoma, and other known cancers that affect epithelial cells throughout the body. The compositions of the present invention are expected to be particularly useful for such types of neoplasia as gastrointestinal cancer, Barrett's esophagus, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, cervical cancer, lung cancer, cancer 65 breast and skin cancers such as squamous cell carcinoma and basal cell carcinoma. The compounds and methods of the present invention can also be used to treat fibrosis caused by radiation therapy. Such compositions can be used to treat patients with adenomatous polyps, including patients with hereditary adenomatous polyps (HAP). In addition, such compositions can be used to prevent the formation of polyps in patients at risk of RGAR. The compounds of the present invention are useful for the treatment of cancer due to their antiangiogenic activity.

Further uses include the treatment of inflammation in diseases such as vascular disease, migraine headache, panarteritis nodosa, goiter, aplastic anemia, Hodgkins disease, scleroderma, rheumatism, type I diabetes, neuromuscular disorders including bulbospinal palsy, white matter diseases including multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, 7/0. "ingivitis, nephritis, allergy, edema caused by trauma, including cerebral edema, myocardial ischemia, and the like. Also includes treatment of ophthalmic diseases such as retinitis, conjunctivitis, retinopathy, uveitis, photophobia, and acute eye tissue injury. Also includes treatment of inflammation of the lungs and inflammation of the upper respiratory tract, such as inflammation associated with viral infections and cystic fibrosis, and in cyst resorption, such as accompanying osteoporosis.These compounds and compositions are useful for /5 Treatment of specified nervous system diseases such as mental retardation, including illness

Alzheimer's disease, neurodegeneration and damage to the central nervous system as a result of stroke, ischemia or trauma. The compounds of the present invention may also be useful in the treatment of Parkinson's disease.

Methods of treating pain include administering to a mammal suffering from such pain a pharmaceutically effective amount of a compound of the present invention, alone or in combination with one or more additional pharmaceutically effective agents for the treatment of pain or inflammation or medically related conditions. Examples of drugs that can be combined with these compounds are analgesics, antiangiogenic drugs, antineoplastic drugs. These compounds can also be combined with antiepileptic compounds having analgesic properties, such as gabapentin and pregabalin.

One such combination method according to the present invention comprises administering to a mammal, if necessary, a pharmaceutically effective amount of a compound according to the present invention and a pharmaceutically effective amount of a non-toxic M-methyl-O-aspartate (MMOA) receptor antagonist and/or blocking agent , at least one of i) the main intracellular activation sequences of the MMOA receptor. Examples of MMOA receptor antagonists useful in these methods include dextromethorphan, dextrorphan, amantadine, and memantine, or pharmaceutically acceptable salts thereof. Another method of treating inflammation and inflammatory diseases involves co-administering to a mammal, if necessary, an inhibitor of inducible nitric oxide synthase with a compound of the present invention. This combination is applicable for prophylactic or therapeutic administration to a mammal experiencing or exposed to an abnormally low level of nitric oxide synthase (NO5) activity, in particular suffering from elevated blood pressure or an increased risk of pulmonary hypertension, ischemic stroke, myocardial infarction, heart failure, progressive kidney disease, thrombosis, reperfusion injury, or degenerative disorders of the nervous system such as Alzheimer's disease, or chronically hypoxic.

The methods of the present invention also include methods of treating or preventing neoplasia in mammals, including humans, in need of such treatment or prevention. The method includes treating a mammal with a therapeutically effective amount of a compound according to the present invention in combination with an MMP inhibitor. These two "

The components may be optionally combined with one or more agents selected from 7-3 of an antiangiogenic drug, an antiblastoma agent, an adjuvant, an immunotherapeutic agent, an analgesic; and/or radiotherapeutic substance. One such multicomponent therapy includes the introduction of; to a mammal, if necessary, a compound according to the present invention, a matrix metalloproteinase inhibitor, and an antineoplastic agent.

The methods and combinations of the present invention can be used for the treatment and prevention of -I neoplasia, including acral lentiginous melanoma, actinic keratosis, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenosarcoma, adenocarcinoma, astrocytic tumor, Bartholiian carcinoma,

Ш- basal cell carcinoma, bronchial gland carcinoma, capillary argentaphinoma, carcinoma, i5" carcinosarcoma, cavernous cholangiocarcinoma, cartilage sarcoma, choroid plexus papilloma/carcinoma, clear cell carcinoma, cystadenoma, endodermal tumor, endometrial hyperplasia, endometrial

Sh- stromal sarcoma, endometrioid adenocarcinoma, ependymal glioma, epithelioid cell sarcoma,

From Ewing's sarcoma, fibrous formation, focal nodular hyperplasia, gastrinoma, germ cell tumor, glioblastoma, glucagonoma, hemangioblastoma, hemangioendothelioma, hemangioma, liver adenoma, hepatic adenomatosis, hepatocellular carcinoma, beta-cell tumor, intraepithelial neoplasia, squamous cell neoplasia , invasive squamous cell carcinoma, large cell carcinoma, leiomyosarcoma, malignant lentigo-melanoma, malignant melanoma, malignant mesothelial tumors, (F, medulloblastoma, medulloepithelioma, melanoma, meningeal, mesothelial, metastatic carcinoma, mucoepidermoid carcinoma, neuroblastoma, neuroepithelial adenocarcinoma, nodular melanoma, oat cell carcinoma, oligodendroglioma, osteosarcoma, pancreatic polypeptide, papillary serous adenocarcinoma, pineal cell tumor, pituitary tumor, plasmacytoma, pseudosarcoma, pulmonary blastoma, hypernephroma, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma noma, small cell carcinoma, soft tissue carcinoma, somatostatin-secreting tumor, squamous cell carcinoma, squamous cell carcinoma, superficial diffuse melanoma, undifferentiated carcinoma, uveal melanoma, warty carcinoma, papoma, well-differentiated carcinoma, and Wilm's tumor. 65 Antiblastoma agents useful in the combination therapies described herein include anastrozole, calcium carbonate, capecitabine, carboplatin, cisplatin, Se! Raiimzh"auz SR-461, docetaxel, doxorubicin, etoposide,

fluorouracil, fluoxymestrin, gemcitabine, goserelin, irinotecan, ketoconazole, letrozole, leucovorin, levamisole, megestrol, mitoxantrone, paclitaxel, raloxifene, retinoic acid, tamoxifen, tioteru, topotecan, toremifene, vinorelbine, vinblastine, vincristine, selenium (selenomethionine), ursodeoxycholic acid , sulindac sulfone, exemestane and eflornithine (OEMO), 1-(4-(2-azepan-1-ylethoxy)benzyl1-2-(4-hydroxyphenyl)-3-methyl-1H-indol-b5-ol (also known as TZE-424) and 2-(4-hydroxyphenyl)-3-methyl-1-(4-(2-piperidin-1-ylethoxy)benzyl/|-1H-indol-5-ol (also known as EKA-923) .

The present invention also includes methods of using the compounds described herein in combination with a protein inhibitor of interleukin-1, such as an antagonist of the II/-1 receptor (I./-Iga) for the prevention or treatment of inflammatory diseases in mammals. Acute and chronic inflammatory diseases in which the mediator is interleukin-1 (I--1), for the treatment of which these methods are of interest, include, but are not limited to, acute pancreatitis; AND! 5; Alzheimer's disease; cachexia/anorexia; asthma; atherosclerosis; chronic fatigue syndrome, fever; diabetes (for example, insulin diabetes); glomerulonephritis; transplant rejection; hemorrhagic shock; hyperalgesia, inflammatory bowel disease; inflammatory conditions of the joints, including osteoarthritis, psoriatic arthritis and rheumatoid arthritis; ischemic injury, including cerebral ischemia (eg, traumatic brain injury, epilepsy, hemorrhage, or stroke, which can lead to neurodegeneration); lung diseases (for example, AKO5); multiple myeloma; multiple sclerosis; myeloma (for example, AMI and SMI) and other leukemias; myopathies (for example, muscle protein metabolism, especially in sepsis); osteoporosis; Parkinson's disease; pain; premature birth; psoriasis; reperfusion injury; septic

SHOCK; side effects of radiation therapy, mandibular joint disease, tumor metastasis; or inflammatory conditions as a result of overexertion, sprained ligaments, cartilage damage, trauma, orthopedic surgery, or infection of other pathological processes.

The present invention also provides a method of administering one or more compounds according to the present invention to a woman, if necessary, to actually prevent or reduce changes in the female reproductive system associated with the onset or continuation of pregnancy. A method of significant prevention or reduction of uterine contractions occurring during pregnancy or associated with menorrhagia is also proposed. These methods i) may optionally include co-administration of a compound according to the present invention with a progesterone, progestin or progestogen agent.

Each of the methods according to the present invention includes administering to the mammal, in need of such treatment, a pharmaceutically or therapeutically effective amount of a compound according to the invention. In the examples of the combination treatment methods described here, it is to be understood that the administration additionally includes a pharmaceutically or therapeutically effective amount of the second pharmaceutical preparation in question. The second or additional pharmacological preparation described here can be administered in doses and regimens known in the art. -

The compounds according to the present invention can also be used in comparable veterinary methods of treatment, especially for veterinary treatment, suppression or alleviation of inflammation and pain. It is understood that these methods are of particular interest for companion animals such as dogs and cats and for use in the treatment of farm mammals such as cattle, horses, mules, donkeys, goats, pigs, sheep, etc. These methods can be used to treat types of inflammation and pain known as

In veterinary medicine, including, but not limited to, pain and inflammation associated with arthritis, joint defects, pla)c joint developmental defects such as hip dysplasia, tendonitis, inflammation of the ligaments, inflammation of the hoof, solid tumor on the leg in a horse and bursitis, or, pain and inflammation associated with surgical;" intervention, accident, injury or illness such as Lyme disease. These compounds can also be used in the treatment of inflammation of the respiratory tract, for example, conditions of asthma, laryngitis, tracheitis, bronchitis, rhinitis or pharyngitis. -I Compounds according to the present invention can also be used in comparable veterinary methods of treatment, especially for the veterinary treatment, suppression or alleviation of inflammation and pain associated with asthmatic conditions. It is clear that these methods are of particular interest to companion animals, such as dogs and cats, especially those suffering from feline asthma. These compounds can also be used in the treatment of respiratory tract inflammation, such as asthma, laryngitis, tracheitis, bronchitis, rhinitis and pharyngitis. The compounds according to the present invention can be used in the veterinary treatment of asthma and asthmatics

He states in combination with other asthma treatments, such as feline asthma, that include oral or injected steroids, cyproheptadine, cyclosporine A, or anti-interleukin-5 antibodies.

Each of these veterinary methods includes administering to the mammal, if necessary, a pharmaceutically effective amount of the compound of the present invention or its pharmaceutically acceptable salt form. The compounds of the present invention may be used for the treatment of humans or animals together with other medicinal (F) drugs or dietary supplements known in the art to treat, suppress or alleviate inflammation or pain. These may include aspirin (including buffered aspirin, aspirin with maalox and enteric-coated aspirin), COX-2 inhibitors such as celecoxib, non-acetylated carboxylic acids such as magnesium salicylate, salicylamide or sodium salicylate, acetic acids such as diclofenac and etodolac, propionic acids such as ibuprofen, naproxen (available in the form of MARKOZUM trademarks

EOSHIRKOKHEMOYA), ketoprofen, KIMAYUSMI I (carprofen), flunixin, meglumine, fenamic acids such as tolfenamic acid, mefanamic acid, meclofenamic acid (AKOSHEI!F) or niflumic acid, enolic acids such as oxyphenbutazone, phenylbutazone, piroxicam or dipyrone, or non-acidic compounds, 65 analogous to nabumetone. Dimethyl sulfoxide (DMSO), orgotein (such as RAGOBEIMF brand orgotein), polysulfated glycosaminoglycans or RB-ZAES (such as ABEOSHAME brand polysulfated glycosaminoglycan), hyaluronic acid and its natural and synthetic analogues, ketorolac trimethamine (such as commercial brand TOKABOI F), EEG OEMEF (piroxicam) or

METASAMO (methoxycam).

Food additives used in human and animal therapy include glucosamines, chondroitin sulfate, methylsulfonylmethane (MSM), and omega-3 fatty acids and other cold-water fish oils. The compounds and methods of the present invention can also be used in conjunction with physical therapy, massage, chiropractic and acupuncture in humans and animals. Each drug and each food additive can be administered to the subject mammal using regimens and effective dosages known in the art.

Claims (44)

The formula of the invention 1. A compound of the formula: tire NN C where: c K is selected from the formulas -"(СНо)-А, -"СНао)д-5-А or -"СНо)-О-А, where A is selected from the groups: oh or : ; ka Be sh opa olaAliiM where O represents C.4-Cs-lower alkyl, C--Cs-lower alkoxy, C3-Seccycloalkyl, -Cez or -(CH»)4-3-Ce»c; C groups are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl, or pyrrolyl groups, each of which is optionally substituted with 1-3, preferably 1-2, substituents independently selected from NN, halogen, -CM, -CHO . МН-С(0)-(С 1-Svalkyl), -MO" or a 5- or b--heterocyclic or heteroaromatic ring containing 1 or 2 heteroatoms, which are selected from O, M or 5; or n is an integer from 0 to 3; « pi is equal to a whole number from 1 to Z; po is equal to a whole number from 0 to 4; - с пз is equal to a whole number from 0 to З; "» pa is equal to a whole number from 0 to 2; " Kh is selected from the chemical bond, -5-, -О-, -«5(0)-, -«5(0)5,- -МН-, - MNO(O)-, -SES-, that Sho - | na - s Another so DAYS; iz Ki is selected from C.-Svalalkyl, C.i-Ceffluorinated alkyl, C3-Secycloalkyl, tetrahydropyranyl, camphoryl, adamantyl, SM, -M(C.4-Svalalkyl)", phenyl, pyridinyl, pyrimidinyl, furyl, thienyl, naphthyl ) enoic, benzo|1.2.5)oxadiazole, 2-oxa-5-azabicyclo|2.2.1|heptanoic, piperazin-2-one or pyrrolyl groups, each of which is optionally substituted 1-3, preferably 1-2, by substituents independently selected from H, halogen, -СМ, -СНО, -СР53, -ОСЕ5, -ОН, S.-Svalkyl, Si--Svalkoxy, -МНо, -М(С.--Svalkyl)», -МН (S.-Svalkyl), 60 -МН-С(0)-(С4-Svalkyl), -MO», -5О5(С4-Svalkyl), -502МН», -50О2МН(С4-Svalkyl), -5025М4(С4 -Szalkyl), -СООН, -бнН.-сСОоОНн, -СНО-М(Si-Svalkyl), -СНО-М(Si-Svalkyl)", -С No-MNo, pyridine, 2-methylthiazole, morpholino, 1-chloro-2-methylpropyl, -C4-C4-thioalkyl, phenyl (optionally substituted by halogens), benzyloxy, -"-C4-C4-alkyl)c(O)CHu" , -"(C4-Svalkil)/OSN", -С(О)МН" or b5 Y and Y or SHE o and z VEN or - X»o selected from -О-, -СН»-, -5-, -50-, -505, -МН-, -СК(0)-, «г 1 from WANI. not) with M dk z» rozy Es i KN. , - writes и из вни , ш- 29 зайны МК КУ т что) т ZDALI al nya or y ko y » Greek TV so VE I Ko is a ring group selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, and the ring group is replaced by a group of the formula -(СНо)щ-СОоН or a mimetic of a pharmaceutically acceptable acid selected from the group consisting of: with KI 5) SHE yah s same SHY: y shi ih zo Z Norka Liu ne s st » ДЯ -.70 sya I zakin PI o osh he bo s shchi y Y PZHLZHU se as o y Y rya i - pe Z ) ZE ' 3 s sht vy me EM - bok ke SCHE h Ed 7 y vij Y 59 -- o poh, ju so Y IN de Ka selected from -SEz, -CHz, phenyl or benzyl, and the phenyl or benzyl group is optionally substituted 1 - With groups selected from C.4-Salkyl, C-Salkyloxy, C.-Sethioalkyl , -SEz, halogen, -OH or -COOH; K is selected from -СЕ3, -СН3, -МНо, phenyl or benzyl, and the phenyl or benzyl group is optionally substituted 1 - With groups selected from C.4-Salkyl, C-Salkyloxy, C.-Sethioalkyl, -CE3, halogen, -OH or -COOH; because | P is selected from -SEz or S.-Svalkilu; and, in addition, Co, optionally substituted with 1 or 2 additional substituents independently selected from nH, halogen, -CM, -CHO, -CE3, -OCE5, -OH, -C4-Salkyl, -C--Salkyloxy, -C4-Svthioalkyl, -MH»o, -M(C.4-Svalkyl)", -MH(S.-Svalkyl), -MH-C(O0)-(C4-Svalkyl) or -MO"; Ez is selected from H, halogen, -CM, -CHO, -CEz, -OSEz, -OH, -C4-Swalkyl, C--Swallowoxy, C.4-Swthioalkyl, -MH", -M(C1-Swalkyl)" , -"MH(S.-Svalkil), -MH-C(0)-(C4-Svalkil) or -MO"; KE. selected from H, halogen, -CM, -CHO, -CEz, -OSE", -"OH, -C4-Svalkylu, -C4-Svalkoxy, -C4-Sethioalkyl, -MH", -MZh(S.-Svalkyl) », -MH(S.-Svalkil), -MH-C(0)-(C4-Svalkil), -MO», -MH-C(0)-M(S.-Szalkil)», -MH-ES (0)-MH(C 4-Salkyl), -MH-C(0)-0-(C4-Salkyl), -502-C4-Salkyl, -5-C3-Secycloalkyl, 70. 7С-СНо-С3-Свcycloalkyl, -5025-С3-Сеcycloalkyl, -505-СН.-С3-Свcycloalkyl, С3-Свcycloalkyl, -Сно-С3-Secycloalkyl, -0О-С3-Сеcycloalkyl, -0-СНо- C3-C8cycloalkyl, phenyl, benzyl, benzyloxy, morpholino or other heterocycles, such as pyrrolidino, piperidine, piperazine, furan, thiophene, imidazole, tetrazole, pyrazine, pyrazolone, pyrazole, imidazole, oxazole or isoxazole, and the rings of each of these K A - groups are optionally substituted by 1-3 substituents selected from the H group, halogen, -CM, -CHO, -CE with, -OH, -С4-Svalkylu, 75 7 Si-Svalkoxy, -МНо, -М(С- -Svalkyl)», -MH(Si-Svalkyl), /-MH-C(O)-(C4-Svalkyl), -MO», -5О5(S.-Svalkyl), -502МН(С4-Svalkyl), - 502M(S.4-Szalkil)" or -OSE"; or a pharmaceutically acceptable salt form thereof. 2. The compound according to claim 1, where K represents -(СНао)-А. 3. Compound according to claim 1 or 2, where n is equal to 0. 4. A compound according to any of claims 1 - З, where A is a group: щ- НЯ! where B and C are as defined in claim 1. 5. A compound according to any of claims 1-4, where B and C independently represent unsubstituted phenyl, pyridinyl, (o)pyrimidinyl, furyl, thienyl or pyrrolyl groups. 6. A compound according to any of claims 1-3, where A is a group: 7. The compound according to any of claims 1-6, where Kz is selected from H, halogen, -СМ, -СНО, -СЕз, -ОН, -С.4-Svalkylu, v. From 7C41-Svalkoxy, -C4-Svthioalkyl, "MH", -M(C--Svalkyl)", -MH(S.-Svalkyl), -MH-C(O)-(C4-Svalkyl) or -MO" -. uh- 8. A compound according to any one of claims 1-7, where CC is selected from H, halogen, -CM, -CHO, -CE3, -OH, -C.4-Cylalkyl, -C.1-Cyloxy, -C.4-Cylthioalkyl, -MN", -MSH (S.4-Svalkil)", -MN(S.-Svalkil),. -MH-C(O)-(C4-Salkyl), -MO", morpholino or other heterocycles such as pyrrolidino, piperidine, piperazine, furan, thiophene, imidazole, tetrazole, pyrazine, pyrazolone, pyrazole, imidazole, oxazole or isoxazole . " 9. Compound according to any of claims 1-8, where K" and KE. are in the 5th and 6th positions of the indole ring. from the village 10. Compound according to any of claims 1-9, where pZ is equal to 1. J 11. A compound according to any one of claims 1-10, where Xo is -O-, -505-, -MH- or -CH»o-. and?" 12. A compound according to any one of claims 1-11, where Co represents a group selected from: with EI - SKD - and sl p as pt -070 sia Me ?z Ve or 25 KISHEe ; or a pharmaceutically acceptable acid mimetic, where pi is 0-2; and Kv and Ka are independently selected from H, halogen, -CM, -CHO, -SEz, -OH, -C.4-Swalkyl, -C4-Swallowoxy, -C4-Swthioalkyl, -MH", -S(C4-Swalkyl )", -MN (C4-Svalkil),. -MH-С(О0)-(С4-Svalkyl) or -MO". 13. The compound according to any of claims 1-12, where pu is 0. 14. The compound according to any of claims 1-13, where -(CH5)44-СОН or a pharmaceutically acceptable acid mimetic is in position 4. 15. The compound according to any of claims 1-14, where claim 1 is equal to 1 or 2. 16. The compound according to any one of claims 1-15, where claim 2 is equal to 0, 1 or 2. 17. The compound according to any of claims 1-15, where claim 1 and claim 2 are equal to 1. 18. A compound according to any one of claims 1-17, where X is selected from the chemical bond, -5-, -O-, -MH- or -Щ(C-Szalkyl)-. 19. A compound according to any of claims 1-18, where C is selected from C-alkyl, C3-Seccycloalkyl, phenyl, pyridinyl, naphthyl, tetrazole, each of which is optionally substituted 1 - With substituents, independently selected with H, halogen, -CM, -CHO, -SEz, -OSE»5, -OH, -C.-Svalkylu, -C4-Svalkoxy, -MH», -M(C.4-Svalkyl)», -MH (S.-Svalkyl), -МН-С(0)-(С4-Svalkyl), -MO", -5О5(С4-Svalkyl), -502МН", -50О2МН(С4-Svalkyl), -5025М4(С4- Szalkil)", - UNO, -СН.-соонН, -СН.-МЩ(С.-Svalkyl), -СНо-М(С.-Svalkyl)», -СНо-МН-С.-Сеthioalkyl, phenyl (optionally substituted by halogens ), benzyloxy, -(C4-Salkyl)c(O)CH", -(C4-Salkyl"/OSN", -C(O)MH". 20. The compound according to any of claims 1-18, where K. has the formula: and where K", Kb, Kv are independently selected from H, halogen, -СМ, -СНО, -СЕз, -ОСЕз, -ОН, С4 -S-alkyl, -C--Svalkoxy, -MH», -MH(C.-Svalkyl)», -MH(C4-Svalkyl),. -MH-С(О0)-(С4-Svalkyl) or -MO". 21. The compound according to claim 1, which has the formula (II) or (1): ич МВ Би ' (И И) и лий меле р ХВ сч ПИ ОВ mika Эх ; (1) - pe " z5 DE WE SHY shin ee Kk shiya ts de p, claim 2, claim 3, claim 4, Hu, Ho, K., K", Ez and K. are as defined in claim 1 , or a pharmaceutically acceptable salt thereof. with" 22. Compound according to claim 21, where claim 3-1. 23. The compound according to claim 21 or 22, where Co is a phenyl substituted by a group of the formula -(CH5)m4-СОН, and optionally substituted by 1 or 2 additional substituents independently selected from H, halogen, -CM, -CHO , - 45 -SEz, -OH, -Si-Svalkylu, -Si-Svalkoxy, -C.-Sestioalkyl, -MNo, -M(C--Svalkyl)», -MH(S.--Svalkyl), -MH -C(0)-(C 1-Svalkil) or -MO". -I 24. The compound according to claim 1, which has the formula (IM) or (M): their M BO M) - "pe she She still TELE vyy still KD their 60 b5 perech what I CY SHK Kk: MY 70 Shara SHA. KK where: claim 1 is equal to a whole number from 1 to 3; claim 2 is equal to a whole number from 1 to 3; K5, Kv and Kv; independently selected from Н, halogen, -СМ, -СНО, -СЕз, -ОН, -С4- Svalkylu, -С4-Svalkoxy, -МН", -М(С4-Svalkyl)", -МН(С.-Svalkyl), -"МН-С(О0)-( Si--Svalkyl) or -MO"; selected from the chemical bond, -5-, -O-, -МН- or -МН(С 1-Salkyl)-; Xo selected from -0-, -3О»- or -H.-; Ko is a group , selected from: se PAN; o ona sch z0 TE tchn ih voyak | - KVK velysty deno i- and where and M nyn Kck Ka and Kj independently selected from H, halogen, -CM, -СНО, -СЕз, -ОН , -S.-Svalkylu, -Si-Svalkoxy, -MH", -M(C1-Svalkyl)", -"MH(S.-Svalkyl), -MH-C(0)-(C4-Svalkyl) or - MO"; claim 4 is equal to a whole number from 0 to 2; "Ez selected from H, halogen, -CM, -CHO, -CE", -OH, -C4-Svalkylu, S.--Svalkoxy, -C.-Sethioalkyl, -MH», -M(C.4-Svalkyl)», -MH(S.-Svalkyl), -MH-C(O0)-(C4-Svalkyl) or -MO»; and - with K; selected from H, halogen, -CM, -CHO, -SEz, -OH, -C4-Salkyl, -C--Salkyloxy, -C,4-Cylthioalkyl, -MH", "from -M(C4-Salkyl)" , -MH(C.-Svalkyl), -MH-C(0)-(C4-Svalkyl), -MO», morpholino or other heterocycles, such as "pyrrolidino, piperidine, piperazine, furan, thiophene, imidazole, tetrazole , pyrazine, pyrazolone, pyrazole, imidazole, oxazole or isoxazole; or a pharmaceutically acceptable salt form thereof. 25. The compound according to claim 1, which has the formula (MI) or (MI): ih perrudnyut i (MO, - i h-" shi she shi shin ko bo b5 Б КН ей, чия , (МИ) п сий и Ш КЕ: where: Хи is selected from a chemical bond, -5-, -О-, -МН- or -МН(С 1-Szalkyl)-; X"o is selected from -O-, -505- or -CH"; Kz is selected from H, halogen, -CM, -CHO, -SEz, -OH, -C4-Cylalkyl, -C--Cyloxy, -C.4-Cylthioalkyl, -MH", -M(C.4-Cylalkyl) », -MH(С.4-Svalkil), -МН-С(О0)-(С.-Svalkil) or -MO»; and K; selected from H, halogen, -CM, -CHO, -SEz, -OH, -C4-Cylalkyl, -C--Cyloxy, -C.4-Cylthioalkyl, -MH", -M(C.4-Cylalkyl)" , -MH(C.-Svalkyl),, -MH-C(0)-(C.-Svalkyl), -MO", morpholino or other heterocycles, such as pyrrolidino, piperidine, piperazine, furan, thiophene, imidazole, tetrazole , pyrazine, pyrazolone, pyrazole, imidazole, oxazole or isoxazole; claim 1 is equal to the whole number from 1 to 2; claim 2 is equal to the whole number from 1 to 2; Ha KB, Kv and Ke are independently selected from H, halogen, -CM, -CHO, -SEz, -OSEz, -"OH, -C4-Svalkylu, -C4-Svalkoxy, -MH", -M(С.4- Svalkyl)", -MH(C.4-Svalkyl), -MH-C(0)-(C4-Svalkyl) or -MO"; i) Ka and K are independently selected from H, halogen, -CM, -CHO, -SEz, -OH, -C.-Svalkyl, -Si-Svalkyl, -MH», -M(С4-Svalkyl)», -MH (S.-Svalkil),, -"МН-С(О0)-(С4-Svalkil)u or -MO"; or a pharmaceutically acceptable salt form thereof. Ge 26. The compound according to claim 25 of the formula (MI) or (MII), where: claim 1 is equal to 1 and claim 2 is equal to 1. - 27. The compound according to any of claims 1-26, where X represents a chemical bond. "AND 28. The compound according to claim 1, which is selected from the group consisting of 4-(2-(1-benzhydryl-2-2-((benzylsulfonyl)amino|ethyl)-5-chloro-1H-indole-3-ylethoxy| benzoic acid; - 4-(2-(1-benzhydryl-5-chloro-2-2-isopropylsulfonyl)amino|ethyl)-1H-indol-3-yl)letoxy|benzoic acid; - 4-(2-(1 -benzhydryl-2-2-((butylsulfonyl)amino|ethyl)-5-chloro-1H-indol-3-yl)ethoxy|benzoic acid; 4-2-P1-benzhydryl-5-chloro-2-(2- X4(1-methyl-1H-imidazol-4-yl)usulfonylamino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid; « 4-2-(1-benzhydryl-2-(2-1(5-bromo-6-chloro-3-pyridinyl)sulfonyl|aminoethyl)-5-chloro-1H-indol-3-yl|ethoxy)bene 70 ZOIC ACID; - c 4-(2-(1-benzhydryl-5-chloro-2-12-ICDC(1K)-7,7-dimethyl-2-oxobicycloi|2.2.1|hept-1-yl|methyl)sulfonyl)amino |et cyl)-1H-indole-3-yl)ethoxy|benzoic acid; "» 4-(2-71-benzhydryl-5-chloro-2-(2-4H(methylsulfonyl)methyl|sulfonyl)amino)ethyl/|-1H-indole-3-ilyethoxy)benzoic acid; 4-(2 -711-benzhydryl-5-chloro-2-(2-4(2-(1-naphthyl)ethyl|sulfonyl)amino)ethyl|-1H-indol-3-ylethoxy)benzoic acid; 4-2-P1 -benzhydryl-5-chloro-2-12-(I(2-nitrobenzyl)sulfonyl)amino|ethyl)-1H-indol-3-yl)ethoxy|benzoic acid; 7 4-2-11-benzhydryl-5-chloro -2-(2-1((3,4-dichlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Iethoxy)benzoic acid; 4-2-11-benzhydryl-5-chloro-2 -(2-Х(3,5-dichlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Iethoxy)benzoic acid; Kz 4-(2-71-benzhydryl-5-chloro-2-( 2-4(3-trifluoromethyl)benzyl|sulfonyl)amino)ethyl/|-1H-indole-3-iliethoxy)benzoic acid; 4-(2-71-benzhydryl-5-chloro-2-(2-4 (4-«(trifluoromethyl)benzyl|sulfonyl)amino)ethyl/|-1H-indole-3-iliethoxy)benzo HNOY ACIDS; 4-2-P1-benzhydryl-5-chloro-2-(2-1(4- fluorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Iethoxy)benzoic acid; (no)ethyl)-1H-indole-3-yl)ethoxy)benzoic acid; 2-(2-(2-aminobenzyl)sulfonyl|aminoethyl)-4-12-(1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy)benzoic acid; in 4-2-P1-benzhydryl-5-chloro-2-(2-Y(dimethylamino)sulfonyl1|amino)ethyl)-1H-indol-3-yl|1ethoxy)benzoic acid; 4-2-11-benzhydryl-5-chloro-2-(2-1(3,4-difluorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid; 4-22-P1-benzhydryl-5-chloro-2-(2-(2-naphthylmethyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid; 65 3-(1(2-11-benzhydryl-3-I(2-(4-carboxyphenoxy)ethyl)|-5-chloro-1H-indol-2-ylethyl)amino|sulfonyl)methyl)benzoic acid; 4-(2-71-benzhydryl-5-chloro-2-(2-4KE)-2-phenylethenyl|Isulfonyl)amino)ethylI-1H-indol-3-ylethoxy)benzoic acid; 4-2-11-benzhydryl-5-chloro-2-(2-Trifluoromethyl)sulfonyl|aminoethyl)-1H-indol-3-yl|ethoxy)benzoic ACID; 4-(2-(1-benzhydryl-5-chloro-2-2-(cyclopropylsulfonyl)amino|ethyl)-1H-indol-3-yl)ethoxy|benzoic acid; 4-(2-711-benzhydryl-2-(2-(1H3,5-bis(trifluoromethyl)benzyl|sulfonyl)amino)ethyl|-5-chloro-1H-indole-3-ilyethoxy)b enoic acid; 2-((2-11-benzhydryl-3-(2-(4-carboxyphenoxy)ethyl/|-5-chloro-1H-indol-2-yl)ethyl)amino|sulfonyl)benzoic P where it is 4-(2 -(1-benzhydryl-5-chloro-2-12-(2-naphthylsulfonyl)amino|ethyl)-1H-indol-3-yl)ethoxy|benzoic acid; 4-2-11-benzhydryl-5-chloro-2-(2-C(3,5-dichlorophenyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid; 4-2-11-benzhydryl-5-chloro-2-(2-1(3,4-dichlorophenyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic /5 ACID; 4-2-11-benzhydryl-5-chloro-2-(2-S(2,3-dichlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid; 4-2-(1-benzhydryl-5-chloro-2-(2-1(2,4-dichlorobenzyl)sulfonyl|amino)ethyl)-IN-indol-3-yl|ethoxy)benzoic acid; 4-2-11-benzhydryl-5-chloro-2-(2-S(2,4-dichlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid; 4-2-P1-benzhydryl-5-chloro-2-(2-S(4-chloro-2-nitrobenzyl)sulfonyl|amino)ethyl)-1H-indole-3-yl|ethoxy)benzoic acid; 4-(2-(1-benzhydryl-2-2-((benzylsulfonyl)amino|ethyl)-5-morpholin-4-yl-1H-indol-3-yl)ethoxy|benzoic acid; 4-2- (1-benzhydryl-5-chloro-2-(2-1(2-cyanobenzyl)sulfonyl|aminoethyl)-1H-indol-3-yl|ethoxy)benzoic acid; i) 4-2-(1-benzhydryl-5 -chloro-2-(2-1(2-cyanobenzyl)sulfonyl|aminoethyl)-1H-indol-3-yl|ethoxy)benzoic acid; 4-2-P1-benzhydryl-5-chloro-2-(2-1(3-cyanobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl)ethoxy)benzoic acid; 4-2-(1-benzhydryl-5-chloro-2-(2-1(4-cyanobenzyl)sulfonyl|aminoethyl)-1H-indol-3-yl|ethoxy)benzoic acid; c zo 4-(2-71-benzhydryl-5-chloro-2-(2-(14-(1-piperidinylsulfonyl)benzyl|sulfonyl)amino)ethyl/|-1H-indole-3-ylethoxy)benzoic acid; - 4-(2-2-(2-44-(aminosulfonyl)benzyl|sulfonyl)amino)ethyl/)|-1-benzhydryl-5-chloro-1H-indole-3-ylethoxy)benzoic acid; 4-(2-71-benzhydryl-5-chloro-2-(2--4-methanesulfonylphenylmethanesulfonylamino)ethyl|-1H-indol-3-ylethoxy)benzyl-oynamic acid; 4-(2-71-benzhydryl-5-chloro-2-(2-(4-diethylsulfamoylphenylmethanesulfonylamino)ethyl/|-1H-indole-3-ilyethoxy)benzoic acid; 4-(3-P1-benzhydryl-5 -chloro-2-(2-phenylmethanesulfonylaminoethyl)-1H-indol-3-yl|Ipropyl)benzoic acid; 4-(3-P1-benzhydryl-5-chloro-2-(2-1(3,5-dichlorobenzyl) sulfonyl|amino)ethyl)-1H-indol-3-yl|propyl)ubenzoic acid; 4-(3-P1-benzhydryl-5-chloro-2-(2-11(3,4-dichlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|propyl)ubenzoic acid; ; » 4-(2-(1-benzhydryl-5-chloro-2-(2-Kmethylsulfonyl)amino|ethyl)-1H-indole-3-yl|ethoxy)benzoic acid; 4-(2-(1-benzhydryl-5-chloro-2-12-(phenylsulfonyl)amino|ethyl)-1H-indole-3-yl|ethoxy)benzoic acid; 4-(2-71-benzhydryl-5-chloro-2-(2-(13-trifluoromethyl)benzyl|sulfonyl)amino)ethyl/|-1H-indol-3-ilyethoxy)benzoic acid; 2-(I(2-((2-11-benzhydryl-3-I(I2-(4-carboxyphenoxy)ethyl)|-5-chloro-1H-indol-2-ylethyl)amino|sulfonyl)ethyl)ami Sh - no|carbonyl)benzoic acid; their 4-2-C1-benzhydryl-5-chloro-2-(2-((3-(pyridinylmethyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic Acid; S-4-2-C1-benzhydryl-5-chloro-2-(2-(1(4-(pyridinylmethyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid; 4-2-C1-benzhydryl-5-chloro-2-(2-(1(2-(pyridinylmethyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid; 4-(3-P1-benzhydryl-5-chloro-2-(2-I((2,6-dimethylbenzyl)sulfonyl|amino)zetyl)-1H-indol-3-yl|Ipropyl)benzoic acid; F) 4-2-11-benzhydryl-5-chloro-2-(2-Y(cyclohexylmethyl)sulfonyl|aminoethyl)-1H-indol-3-yl|ethoxy)benzoic acid; 4-2-P1-benzhydryl-5-chloro-2-(2-I(4-nitrobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid; in 4-2-P1-benzhydryl-5-chloro-2-(2-I(3-nitrobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid; 4-2-1P1-benzhydryl-5-chloro-2-(2-(1(2-nitrobenzyl)sulfonyl)amino|ethyl)-1H-indol-3-yl)ipropyl|benzoic acid; 4-(3-P1-benzhydryl-5-chloro-2-(2-1(4-fluorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Ipropyl)benzoic acid; 4-(3-71-benzhydryl-5-chloro-2-(2-(14-trifluoromethyl)benzyl|sulfonylamino)ethyl-1H-indol-3-yl)ipropyl)benzoic acid; 65 4-(3-71-benzhydryl-5-chloro-2-(2-(13-trifluoromethyl)benzyl|sulfonylamino)ethyl-1H-indol-3-yl)ipropyl)benzoic acid; 4-(3-P1-benzhydryl-5-chloro-2-(2-S(4-chlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Ipropyl)benzoic acid; 4-(3-P1-benzhydryl-5-chloro-2-(2-S(2-pyridinylmethyl)sulfonyl|aminoethyl)-1H-indol-3-yl|Ipropyl)benzoic acid; 4-(3-P1-benzhydryl-5-chloro-2-(2-I(3-pyridinylmethyl)sulfonyl|aminoethyl)-1H-indol-3-yl|Ipropyl)benzoic acid; 4-(3-P1-benzhydryl-5-chloro-2-(2-I(4-pyridinylmethyl)sulfonyl|aminoethyl)-1H-indol-3-yl|Ipropyl)benzoic acid; 4-(3-P1-benzhydryl-5-chloro-2-(2-S(2-chlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Ipropyl)benzoic acid; 70 4-(3-P1-benzhydryl-5-chloro-2-(2-I(3-nitrobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Ipropyl)benzoic acid; 4-(3-P1-benzhydryl-5-chloro-2-(2-1(3-chlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Ipropyl)benzoic acid; 4-(3-P1-benzhydryl-5-chloro-2-(2-S((2,5-dichlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|propyl)ubenzoic acid; 4-(3-P1-benzhydryl-5-chloro-2-(2-1(3-methoxybenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|propyl)benzoic acid; 4-(3-I2-(2-(2-aminobenzyl)sulfonyl|amino)ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|Ipropyl)ubenzoic acid; 4-(3-P1-benzhydryl-5-chloro-2-(2-S(2-methylbenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|propylbenzoic acid; 4-2-11-benzhydryl-5-chloro-2-(2-1(4-trifluoromethoxybenzyl)sulfonyl|amino)ethyl)-1H-indole-3-yl|ethoxy)benzoic acid; 4-22-P1-benzhydryl-5-chloro-2-(2-C1(2-fluoro-6-nitrobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid; 4-2-P1-benzhydryl-5-chloro-2-(2-S(2-dichlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid; c 4-2-11-benzhydryl-5-chloro-2-(2-S(2,6-difluorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid; i) 4-(2-71-benzhydryl-5-chloro-2-(2-4(b-chloro-3-pyridinyl)methyl|sulfonylamino)ethyl|-1H-indol-3-yl)ethoxy)benzoic acid ; 4-(2-71-benzhydryl-5-chloro-2-(2-4((5,6-dichloro-2-pyridinyl)methyl|sulfonyl)amino)ethyl/|-1H-indol-3-yl)ethoxy c zo ) benzoic acid; 4-2-11-benzhydryl-5-chloro-2-(2-I(3-methoxybenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid; "E 4-2-P1-benzhydryl-5-chloro-2-(2-I(3,5-dimethylbenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Iethoxy)benzoic acid; - 4-2-11-benzhydryl-5-chloro-2-(2-S(2-methylbenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid; 4-2-11-benzhydryl-5-chloro-2-(2-S(2,6-dichlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)benzoic acid; 4-(2-H-benzhydryl-5-chloro-2-(2-H((phenylsulfanyl)methyl|sulfonyl)amino)ethyl/1-1H-indole-3-ylylethoxy)benzoic acid; with c 4-(2-711-benzhydryl-5-chloro-2-(2-(-2,6-dimethylphenylsulfanylmethanesulfonylamino)ethyl|-1H-indol-3-yl)ethoxy)b . enzoic acid; and?" 4-(2-711-benzhydryl-5-chloro-2-(2-(2-methoxyphenylsulfanylmethanesulfonylamino)ethyl/|-1H-indole-3-ilyethoxy)benzoic acid; 4-(2-71-benzhydryl-5- chloro-2-(2-(2-chloro-6-methylphenylsulfanylmethanesulfonylamino)ethyl/|-1H-indole-3-iliethox-1 i)benzoic acid; 4-(2-71-benzhydryl-5-chloro-2-( 2-(3,5-dichlorophenylsulfanylmethanesulfonylamino)ethyl/|-1H-indole-3-iliethoxy)benzoic acids; their 4-(2-711-benzhydryl-5-chloro-2-(2-(3,4- dimethoxyphenylsulfanylmethanesulfonylamino)ethyl|-1H-indol-3-yl)ethoxy)benzoic acid; -1H-indole-3-ylethoxy)benzoic acid; 4-(2-71-benzhydryl-5-chloro-2-(2-(2-pyrazol-1-ylethanesulfonylamino)ethyl-1H-indole-3-ylethoxy) benzoic acid; 4-(2-711-benzhydryl-5-chloro-2-(2-(2-phenylaminoethanesulfonylamino)ethyl|-1H-indol-3-yl)ethoxy)benzoic acid; F) 4-(2-71 -benzhydryl-5-chloro-2-(2-(412-(1,4-dioxa-8-azaspiro|4.5)dec-8-yl)ethyl|sulfonyl)amino)ethyl|-1H-indo cal-Z -yl)ethoxy)benzoic acid you; 4-(2-(1-benzhydryl-5-chloro-2-12-((2-14-(2-pyridinyl)-1-piperazinyl|ethyl)isulfonyl)amino|ethyl)-1H-indole-3-y for p)ethoxy|benzoic acid; 4-(2-71-benzhydryl-5-chloro-2-(2-412-(1H-1,2,4-triazol-1-yl)ethylIisulfonyl)amino)ethyl|-1H-indol-3-yl) ethoxy) benzoic acid; 4-(2-71-benzhydryl-5-chloro-2-(2-412-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl|sulfonyl)amino)ethylI-1H-indol-3-yl ) ethoxy)benzoic acid; 65 4-(2-711-benzhydryl-5-chloro-2-(2-(42-(3Z-methyl-1H-pyrazol-1-yl)ethyl|sulfonyl)amino)ethyl/)-1H-indole-Z -yl)ethok of sy)benzoic acid; 4-(2-711-benzhydryl-5-chloro-2-(2-(12-(4-methyl-1H-pyrazol-1-yl)ethyl|sulfonyl)amino)ethyl)-1H-indole-3- Si)benzoic acid il)ietok; 4-(2-(1-benzhydryl-5-chloro-2-12-((2-(2K,65)-2,6-dimethyl-1-piperidinyl|ethylsulfonyl)amino|ethyl)-1H-indole-3 -yl)ethoxy|benzoic acid; 4-(2-71-benzhydryl-5-chloro-2-(2-(12-(2-thioxo-1-imidazolidinyl)ethyl|sulfonyl)amino)ethyl/|-1H- indole-3-yl)ethoxy)benzoic acid; 4-(2-711-benzhydryl-5-chloro-2-(2-(12-(1,3-thiazolidin-3-yl)ethyl|sulfonylamino)ethyl|-1H-indol-3-yl)ethoxy)b enzoic acid; 70 4-(2-711-benzhydryl-5-chloro-2-(2-(2-(1,2,3|Igriazol-1-ylethanesulfonylamino)ethyl|-1H-indol-3-yl)oethoxy)benzoin acid; 4-(3-71-benzhydryl-5-chloro-2-(2-(2-morpholine-4-ylethanesulfonylamino)ethyl/|-1H-indole-3-ylpropyl)benzoic acid; 4-I3-(1 -benzhydryl-5-chloro-2-12-(2-(2,6-dimethylpiperidin-1-yl)ethanesulfonylamino|ethyl)-1H-indol-3-yl)propyl Ibenzoic acid; 4-I3-(1-benzhydryl -5-chloro-2-12-(2-(3,5-dimethylpyrazol-1-yl)ethanesulfonylamino|ethyl)-1H-indol-3-yl)propyl|O enoic acid; 4-(2-71-benzhydryl -5-chloro-2-(2-(2-tetrazol-2-ylethanesulfonylamino)ethyl-1H-indol-3-yl)ethoxy)benzoic acid; 4-(2-71-benzhydryl-5-chloro-2-( 2-(2-tetrazol-1-ylethanesulfonylamino)ethyl-1H-indol-3-yl)ethoxy)benzoic acid; 4-2-(1-benzhydryl-b6-chloro-2-(2-phenylmethanesulfonylaminoethyl)-1H-indole -3-yl|ethoxy)benzoic acid; 4-(2-71-benzhydryl-b-chloro-2-(2-(3,4-dichlorophenylmethanesulfonylamino)ethyl|-1H-indol-3-ylethoxy)benzoic acid; c 4-(2-71-benzhydryl-b-chloro-2-(2-(3,5-dichlorophenylmethanesulfonyl) (no)ethyl|-1H-indol-3-ylethoxy)benzoic acid; i) 4-2-(1-benzhydryl-5-chloro-2-(2-1(2-cyanobenzyl)sulfonyl|aminoethyl)-1H-indol-3-yl|ethoxy)benzoic acid; 4-2-P1-benzhydryl-5-chloro-2-(2-I(tetrahydro-2H-pyran-2-ylmethyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethoxy)|benzoic acid; 4-2-11-benzhydryl-2-(2-(1,3-benzoxazol-2-ylmethyl)sulfonyl|amino)ethyl)-5-chloro-1H-indol-3-yl|ethoxy)benzoic acid ; - 4-2-11-benzhydryl-5-chloro-2-(2-I(cyanomethyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Iethoxy)benzoic acid; "g 4-2-11-benzhydryl-5-chloro-2-(2-C(3-thienylmethyl)sulfonylamino)ethyl)-1H-indole-3-yl|1ethoxy)benzoic acid; 4-(2-(1-benzhydryl-5-chloro-2-12-(2-(2-methylpyrrolidin-1-yl)ethanesulfonylamino)ethyl)-1H-indol-3-yl)ethoxy|benzoic acid; i- 4-(2-(1-benzhydryl-5-chloro-2-12-(2-(2-methylpiperidin-1-ylloethanesulfonylamino|ethyl)-1H-indol-3-yl)ethoxy|benzoic acid; 4 -(2-(1-benzhydryl-5-chloro-2-12-(2-(2,5-dimethylpyrrolidin-1-ylloethanesulfonylamino|ethyl)-1H-indol-3-yl)ethoxy Ibenzoic acid; « 4-( 2-71-benzhydryl-5-chloro-2-(2-(2-thiomorpholin-4-ylethanesulfonylamino)ethyl/|-1H-indole-3-iliethoxy)benzoic acid; 4-(2-711-benzhydryl -5-chloro-2-(2-(2-piperidin-1-ylethanesulfonylamino)ethyl|-1H-indol-3-yl)ethoxy)benzoic acid; 4-2-P1-benzhydryl-5-chloro-2 -(2-o-tolylsulfanylmethanesulfonylaminoethyl)-1H-indol-3-yl|Iethoxy)benzoic ACID; -And 4-(2-711-benzhydryl-5-chloro-2-(2-(2-chlorophenylsulfanylmethanesulfonylamino)ethyl)|- 1H-indol-3-yl)ethoxy)benzoic acid; Ш-4-(2-71-benzhydryl-5-chloro-2-(2-(2,6-dichlorophenylsulfanylmethanesulfonylamino)ethyl/|-1H-indole-Z 4-(2-71-benzhydryl-5-chloro-2-(2-(2,5-dimethoxyphenylsulfanylmethanesulfonyl-amino)ethyl/|-1H-indole-3-ylethoxy)benzoic acids; He 4- (2-(1-benzhydryl-5-chloro-2-12-(2-(3-hydroxypyrrolidin-1-yl)ethanesulfonylamino|ethyl)-1H-indol-3-yl)ethoxy|) benzoic acid; 4-(2-(1-benzhydryl-5-chloro-2-12-(2-(4-hydroxypiperidin-1-yl)ethanesulfonylamino|ethyl)-1H-indol-3-yl)ethoxy 5B benzoic acid; 4- (2-71-benzhydryl-5-chloro-2-(2-(2-pyrrolidin-1-ylethanesulfonylamino)ethyl/1-1H-indole-3-ylethoxy)benzoic (F, acid; ka 4-(2-( 1-benzhydryl-5-chloro-2-12-(2--2-dimethylaminomethylpiperidin-1-yl)ethanesulfonylamino|ethyl)-1H-indole-3-yl)ethoxy|benzoic acid; in 4-(2-711 -benzhydryl-5-chloro-2-(2-(2-imidazol-1-ylethanesulfonylamino)ethyl|-1H-indol-3-yl)ethoxy)benzoic acid; 4-(3-P1-benzhydryl-5-chloro- 2-(2-H1(2,6-difluorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|propyl)ubenzoic acid; 4-(3-P1-benzhydryl-2-(2-1(3 ,4-dichlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|propyl)ubenzoic acid; 65 3-I4-(42-(/1-benzhydryl-5-chloro-2-(2-1( 2-chlorobenzyl)sulfonyl (amino)ethyl)-1H-indol-3-yl)phenyl)propanoic acid; 3-(4-4C2-(1-benzhydryl-2-2-((benzylsulfonyl)amino|ethyl)-5-chloro-1H-indol-3-ylethyl|sulfonyl)phenyl)propanoic acid; 3-I4-(42-(1-benzhydryl-5-chloro-2-(2-1(2,6-difluorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethyl)isulfonyl)phenyl| propanoic acid; 3-I4-(42-(/1-benzhydryl-5-chloro-2-(2-1(2-fluorobenzyl)sulfonyl|amino)ethyl)-IN-indol-3-yl ethyl)sulfonyl)phenyl|propanoic acid ; 3-I4-(42-(/1-benzhydryl-5-chloro-2-(2-1(2-chlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|Hyethylusulfonyl)phenyl|propanoic acid ; 70 4-(4(1-benzhydryl-2-2-((benzylsulfonyl)amino|ethyl)-5-chloro-1H-indol-3-yl)umethyl|iamino)methyl)benzoic acid; 4-(2-(1-benzhydryl-2-(2-Kbenzylsulfonyl)amino|ethyl)-5-chloro-1H-indol-3-yl)ethyl|isulfonyl)benzoic acid; 4-(12-(1-benzhydryl-5-chloro-2-(2-((2-chlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethyl)sulfonyl)benzoic acid; 4-(12-(/1-benzhydryl-5-chloro-2-(2-(1(2,6-difluorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-yl|ethyl)usulfonyl)benzoic acid acids; 4-(12-(/1-benzhydryl-5-chloro-2-(2-(1(2-fluorobenzyl)sulfonyl|aminoethyl)-1H-indol-3-yl|Hyethyl)sulfonyl)benzoic acid; 4- (2-71-benzhydryl-5-chloro-2-(2-(2-pyrrolidin-1-ylethanesulfonylamino)ethyl/1-1H-indole-3-iliethoxy)benzoic acid; 4-(12-(/1-benzhydryl) -5-chloro-2-(2-((3,4-dichlorobenzyl)sulfonyl|amino)ethyl)-1H-indol-3-ilyethyl)usulfonyl)benzoic acid; 4-(12-(/1-benzhydryl- 5-Chloro-2-(2-(1(2,6-dimethylbenzyl)sulfonyl|amino)ethyl)-1H-indol-3-ilyethylIisulfonyl)benzoic acid and 4-(2-(1-benzhydryl-2- 13-(benzylsulfonyl)amino|propyl)-5-chloro-1H-indol-3-yl)ethoxy|benzoic acid; i) and its pharmaceutically acceptable salt form. 29. A pharmaceutical composition containing the compound specified in any of claims 1-28, or its pharmaceutically acceptable salt form and a pharmaceutically acceptable carrier. with zo 30. A method of treating inflammation in a mammal, which comprises administering to a mammal in need thereof a pharmaceutically effective amount of the compound specified in any one of claims 1-28, or a pharmaceutically acceptable salt form thereof. - 31. A method of treating pain in a mammal, in which an effective amount of g of the compound specified in any of claims 1-28, or a pharmaceutically acceptable salt form thereof, is administered to the mammal in need thereof. 32. A method of treating asthma in a mammal, according to which a pharmaceutically effective amount of the compound according to any of claims 1-28 or its pharmaceutically acceptable salt form is administered to a mammal in need thereof. uh- 33. A method of treating arthritic and/or rheumatic disorders in a mammal, in which a pharmaceutically effective amount of a compound according to any one of claims 1-28 or a pharmaceutically acceptable salt form thereof is administered to a mammal in need thereof. 34. The method of claim 33, wherein the disorder is rheumatoid arthritis. " 35. The method of claim 33, wherein the disorder is osteoarthritis. with p 36. The method of claim 33, wherein the disorder is Steele's disease. . 37. The compound of the formula (A) schi » in vil ry B (A) -I sia Jhe: Ent de Ho, p, claim 1, claim 2, claim 3, claim 4, K, KK, Ko, Kz and KA are as defined in any of claims 1-20; and -i 20 K selected from the group consisting of -OH, -MH-5(O) 2-(СНо)po-halogen, -МН-5(0)2-СНАСН»о, -МНо or a protected form - MN". о 38. The compound according to claim 37, which has the formula (B): ШЕНЯ (c) ШЕ ШЕ ШЕ ШЕ ШЕ ШЕ ШЕ ШЕ ШЕ ШЕ ШЕ ШЕ ШЕ ШЕ ШЕ ШЕ ШЕ ШЕ ШЕ ШЕ ООО, where К is -(СН 2) 2-А, -««СНао)д-5 -А or -СНо)п-О-А, where A represents: b5 shcha or PA; O represents S.-Svalkil, Si--Svalkoksy, -SEz or -S.-Szalkil-SEz; B and C are independently selected from the group consisting of a phenyl, pyridinyl, pyrimidinyl, furanyl, thiophenyl or pyrrolyl group, each of which is optionally substituted 1-3, preferably 1-2, by substituents independently selected from the group consisting of H, halogen, -СМ, -СНО, -СЕ з, -ОСЕз, -ОН, -С.-Svalkilu, -С.-Svalkoxy, -МНо, -М(С.4-Svalkyl)", -МН(С.--Svalkyl), -МН-С(0)-(С4-Svalkyl), -MO" or 5 - or b-membered heterocyclic or heteroaromatic ring containing 1 or 2 heteroatoms selected from 0, M or 5; K is selected from the group consisting of -OH, -МН-5(О) 2-(СНо)по-halogen, -МН-5(0)2-СНАСН»о, -МНо or the protected form -МН»; Ka and Ko are independently selected from H, halogen, -CM, -CHO, -SEz, -OSEz, -OH, -C4-Svalkylu, S.-Svalkoxy, -S.-Sestioalkyl, -MN», -M(S.4-Svalkyl)», -MN(S.-Svalkyl),. -MH-C(O0)-(C4-Svalkyl) or -MO"; K7 is -(CH 2)claim 4-СО2Н, C.-Svalyl ether -"СНо)pa-СО2Н or a pharmaceutically acceptable acid mimetic or mimetic compound; Ez is selected from H, halogen, -СМ, -СНО, -СЕз, -OSE", -"OH, -C4-Svalkylu, -C4-Svalkoxy, -C4-Sethioalkyl, -MH", -M(C.4-Svalkyl)", -MH(C.4-Svalkyl), -MH -C(0)-(C4-Svalkyl) or -MO"; KE. selected from H, halogen, -CM, -CHO, -CEz, -OSE", -"OH, -C4-Svalkylu, -C4-Svalkoxy, -C4-Sethioalkyl, -MH", -MZh(S.-Svalkyl) », -MH(C.-Svalkyl), -MH-C(O0)-(C4-Svalkyl), -MO», -MH-C(0)-M(C4-Svalkyl)2, -MH-ES( 0)-MH(C 4-Salkyl), -MH-C(0)-0-(C4-Salkyl), -502-C4-Salkyl, -5-C3-Seccycloalkyl, -3-СНо-С3-Cscycloalkyl, -5025-С3-Secycloalkyl, -5025-СНо-С3-Свcycloalkyl, С3-Свcycloalkyl, -Сно-С3-Secycloalkyl, -0О-С3-Secycloalkyl, -0-СНо-С3-Свcycloalkyl, phenyl, benzyl, benzyloxy, morpholino c or other heterocycles, such as pyrrolidino, piperidine, piperazine, furan, thiophene, imidazole, tetrazole, Ge) pyrazine, pyrazolone, pyrazole, imidazole, oxazole or isoxazole, and the rings of each of these groups are optionally substituted with 1-3 substituents, selected from the group H, halogen, -CM, -CHO, -CE with, -OH, -S.-Svalkylu, -Si-Svalkoxy, -MNo, -M(S.i-Svalkyl)", -MH(S. --Svalkyl), -МН-С(О0)-(С4-Svalkyl), -MO», -5ОЩЩ(С.-Szalkyl), -502МН(С4-Szalkyl), -5024(С14-Szalkyl)» or - OSE»z; c n is equal to a whole number from 0 to 3; rch- claim 1 is equal to a whole number from 0 to 3; claim 2 is equal to a whole number from 0 to 3; in pZ is equal to a whole number from 0 to 3; - claim 4 is equal to the whole number from 0 to 2; and Zo X represents a binding group selected from the group consisting of -O-, -СНо-, -505-, -МН- and -Х(С.4-Svalkyl)-. - 39. The compound according to claim 37, which has the formula (C): dme (c) « - M o IY ih ! pi where: -| 50 Ez, Ku, K, Ku. o, X, claim 1, claim 2 and claim 4 are as defined in claim 37, and "with Co, Kch41, Ki", Kuid and Ki5 are independently selected from the group consisting of H, halogen, -CM, - СНО, -СЕ з, -ОСЕГ», -ОН, -С.4-Svalkilu, -С4-Svalkoxy, -МН», -Ш(С.-Svalkil)», -МН(С.4-Svalkil), - "МН-С(О0)-(С4-Svalkyl), -MO" or a 5- or b--linked heterocyclic or heteroaromatic ring containing 1 or 2 heteroatoms selected from O, M or 5. 40. The compound according to any of claims 37-39, where the halogen atom in the K' group -MH-5(0)2-(СНо)дпо-halogen is bromine (HF) or chlorine. 7 41. The compound according to claim 37, which has the formula (0): 60 b5 vda elk i ВВ о ШЕ с НИ where Х, пи, Ку, К, and Ка.45 are as defined in claim 37. 15 42. The compound according to claim 37, which has the formula (E): t pl r SE) h ME sn: UNK ши Ши сч 25 ЕН Ш На 7 ШЧА : NK Elyale anna NN o where X, Kz and K are such as defined in claim 37, and K40-Ki5 are independently selected from H, halogen, -SM, -CHO, -SE»z, sem 30 -OSE»z, -OH, -C4-Svalkylu, -C4-Svalkoxy, -MH» , -M(С.4-Svalkil)», -МН(С.-Svalkil),, -«МН-С(О0)-(С.-Svalkil), -MO», m or 5- or b-- linoleic heterocyclic or heteroaromatic ring containing 1 or 2 heteroatoms selected from О, Mi5. " 43. The compound according to any of claims 39 - 42, where K40-Ki5 are N. m 44. The compound according to claim 37, which is one of the following: 35 methyl ester of 4-12-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl)ethanesulfonyl)ubenzoic acid ; 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|ethoxy) benzoic acid methyl ester; 4-(3-(2-( 2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl|propyl)benzoic acid; 4-2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H) methyl ester 4-(12-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-ylethylamino)benzoic acid methyl ester. 40 45. The method of obtaining the compound defined in claim 1, according to which: - c a) the reaction of the compound of the formula A is carried out with talu iy ekdit' (A) BIJ SCHE SHK iz de Ho, p. claim 1, claim 2, claim 3, claim 4, K, K", Kz and K. are as defined in claim 1; and K is MH", with a sulfonyl halide of the formula - halogen-ZO(СНо)voХ Ri, Kz where halogen is a suitable halogen and claim 2, X 4 and Ki are as defined in claim 1, leading to the receipt of the corresponding compound of formula (I), or a) carry out the reaction of the compound of formula A; svi dna, pobshtogi BB so SHE ENN de Ho, n, claim 1, po, pZ3, pa, K, K», Kz i K, are as defined in claim 1; and CC is -МН-5(0) 5-(СНо)po-halogen or -МН-5(0)2-СНАСН", and claim 2 is as defined in claim 1, with a nucleophile of the formula: b5 НК , where X and Ku are as defined in claim 1. Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2006, M 12, 15.12.2006. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. with (8) s ich- " cha i - shi s ;" -I -I sh» - 50 Ko) F) name) 60 b5